JAMDA 15 (2014) 607.e5e607.e12

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Original Study

Immunogenicity and Safety of Intradermal Trivalent Influenza Vaccination in Nursing Home Older Adults: A Randomized Controlled Trial Tuen-Ching Chan MBBS, FHKAM a, b, *, Ivan Fan-Ngai Hung MD c, Kwok-Hung Chan PhD d, Clara Pui-Yan Li BSc d, Patrick Tsz-Wai Li BSc d, James Ka-Hay Luk MBBS a, Leung-Wing Chu MD b, Felix Hon-Wai Chan MB Bch a a

Department of Medicine and Geriatrics, TWGHs Fung Yiu King Hospital, Hong Kong SAR, China Division of Geriatrics, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China Division of Infectious Disease, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China d Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China b c

a b s t r a c t Keywords: Influenza vaccination intradermal vaccination immunogenicity safety randomized controlled trial nursing home older adults

Objective: To compare the immunogenicity and safety between full-dose (15 mg) intramuscular (IM) and full-dose (15 mg) intradermal (ID) immunization of the trivalent influenza vaccine in nursing home older adults. Design: A single-center, randomized, controlled, open-label, parallel group trial from October 2013 to April 2014. Setting: Nine nursing homes in Hong Kong. Participants: Hundred nursing home older adults (mean age: 82.9  7.4 years). Intervention: Fifty received ID (Intanza) and 50 received IM (Vaxigrip) vaccination. Measurements: Baseline measurements included demographics, comorbidity, frailty and nutritional status. Day 21 and day 180 immunogenicity (seroconversion rate, seroprotection rate, geometric mean titer [GMT] fold increase in antibody titer) using hemagglutination-inhibition and adverse events were measured. Noninferiority and superiority of ID compared with IM vaccination in immunogenicity were analyzed. The study was registered on ClinicalTrials.gov; identifier: NCT 01967368. Results: At day 21, noninferiority in immunogenicity of the ID vaccination was demonstrated. The seroconversion rate of the H1N1 strain was significantly higher in the ID group. At day 180, immunogenicity of both groups fell but the GMT of all strains in ID group was higher and the difference was significant for H3N2 strain. The seroconversion rate and GMT fold increase of H3N2 strain was significantly higher in the ID group. Local adverse events was significantly more in ID group, but they were mild and resolved in 72 hours. Conclusions: ID vaccination is noninferior, and even superior in some parts of immunogenicity assessment, to IM vaccination without compromising safety in nursing home older adults. ID vaccination is a good alternative to IM vaccination in this population. Ó 2014 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

Influenza infection affects all age groups with the highest incidence of influenza related mortality and morbidity in older adults.13 About 85% of the all-cause mortality attributed to seasonal influenza occurs in older adults.4 Influenza vaccination is the cornerstone of

The authors declare no conflicts of interest. * Address correspondence to Tuen-Ching Chan, MBBS, FHKAM, Division of Geriatrics, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Rd, Hong Kong SAR, China. E-mail address: [email protected] (T.-C. Chan).

influenza prevention. Observational studies and systematic reviews suggest that it can significantly reduce hospitalization and mortality, especially during seasons with good match between circulating and vaccine strain.58 However, its efficacy has been challenged by different reviews.9 A major reason is immunosenescence in older adults, which contributes to unsatisfactory immune response toward influenza vaccine.10 Antibody responses to influenza vaccination have been estimated to be 2- to 4-fold lower in older adults.11,12 Several approaches have been investigated to improve immunogenicity of influenza vaccination, including use of an adjuvant,13,14 increasing the

1525-8610/$ - see front matter Ó 2014 AMDA e The Society for Post-Acute and Long-Term Care Medicine. http://dx.doi.org/10.1016/j.jamda.2014.05.002

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doses of antigens,15,16 and use of new route of vaccine administration. Intradermal administration of influenza vaccine has been suggested to be able to improve immune response because of the abundance of immunostimulatory cells, such as dendritic cells in the dermis.1719 They have an important role in capturing and presenting antigens to the cells of adaptive immune system. They also have a rich supply of blood and lymphatic vessels, which allows circulation of immune cells. Intradermal administration of influenza vaccine has been shown to have comparable or even superior immune response compared with intramuscular administration in healthy older population, and the rates of adverse events postvaccination are also comparable between them.2025 The immunogenicity of intradermal administration has also been shown to be better in immunocompromised patients like organ transplant recipients and patients with chronic obstructive pulmonary disease.2629 In addition, intradermal vaccination has good acceptability and safety profile in different countries.3033 Nursing home older adults is a homogeneous subgroup of geriatric population with different personal and environmental characteristics.3436 Many of them have malnutrition, multiple comorbidity, and functional impairment.37 Hence, they are frail, functionally dependent, immunocompromised, and more vulnerable to complications from influenza infection such as more hospitalization and mortality compared with younger adults.38,39 Moreover, they are susceptible to infection because of the crowded institutional environment within which older adults socialize and live. The crowded living environment, shared physical therapy activities, shared bathing equipment, and group dining facilities have the potential to foster person-to-person transmission of infectious agents and predispose spreading and outbreak of influenza infection.40,41 Hence, influenza vaccination in this population is even more important. Nevertheless, most studies for intradermal influenza vaccination were performed for community dwelling older adults. To our knowledge, there is no study regarding the immunogenicity of intradermal influenza vaccination in nursing home older adults, who are commonly frail and immunocompromised. We, therefore, would like to perform an open labeled, randomized study to compare the safety and immunogenicity between conventional full dose intramuscular and full dose intradermal immunization of the 2013/2014 trivalent influenza vaccine in nursing home older adults. Methods This single-center, randomized, controlled, open-label, parallel group study with intention to treat analysis was carried out in the Fung Yiu King Hospital of Hong Kong from October 2013 to April 2014. We compared the immunogenicity and safety of a single fulldose (15 mg) intradermal (ID) trivalent influenza vaccine (TIV) with a single full-dose (15 mg) intramuscular (IM) TIV. The vaccine used was Intanza (Sanofi-Pasteur, Lyon, France) for the ID group and Vaxigrip (Sanofi-Pasteur, Lyon, France) for the IM group. Both of them were designed and approved for use in Hong Kong, the United States, and most European cities. The TIV used was an inactivated, nonadjuvanted vaccine formulated to contain 15 mg of hemagglutinin of influenza A/Victoria/361/2011 (H3N2)-like virus, influenza A/California/7/2009 (H1N1)-like virus, and influenza B/Massachusetts/2/2012like virus. Participants were recruited from 9 nursing homes located in Hong Kong West Cluster, Hospital Authority. Inclusion criteria were nursing home older adults age of 65 or above from one of the 9 nursing homes who satisfied the 3. World Health Organization recommendation for annual vaccination against influenza. Exclusion criteria includes acute febrile illness; hypersensitivity to egg or chicken proteins or any of the vaccine constituents; thrombocytopenia or a bleeding disorder contraindicating intramuscular vaccination; unstable chronic illness; and dementia. Older adults were also

excluded if they had received immunosuppressive therapy within the previous 6 months or received systemic steroid for more than 1 month within the previous 6 months. Older adults fulfilling the inclusion criteria were screened by the principal investigator. After explanation of study protocol to nursing home older adults and their relatives by the principal investigator, they were allowed to have 1 week to consider joining the study. After written informed consent by the participants and family members, participants were assigned by a randomization list generated using a 1:1 ratio based on balanced permuted blocks stratified by centre. Group ID received full dose ID TIV using BD Soluvia device (Becton Dickinson, Franklin Lakes, NJ), which consists of prefilled trivalent influenza vaccine with a single 1.5-mm needle penetrating perpendicularly to the skin.24,42 Group IM received the full-dose standard IM TIV. The principal investigator who did not take part in the subsequent assessment of immunogenicity performed all the vaccination procedures. Upon administration of the vaccine, the following data were also collected from participants: (1) age and sex; (2) vaccination history of seasonal influenza vaccine 2012/2013; (3) comorbidities measured by Charlson comorbidity index, which were validated previously for quantifying comorbidities in Chinese older adults43; (4) frailty index using Canadian Study of Health and Aging (CSHA) clinical frailty scale and Cardiovascular Health Survey (CHS) phenotypic definition, which are both validated for quantifying frailty in older adults4448; (5) nutritional status using body mass index and serum albumin level, which are associated with mortality and morbidity in Chinese older adults49; and (6) serum creatinine level 3 months within the study period, which is associated with mortality and morbidity in Chinese older adults and may affect efficacy of influenza vaccine.5052 Antibody titers were measured using hemagglutination inhibition (HAI) assays according to standard methods as described previously, at baseline, 21 days, and 180 days after vaccination, in the laboratory of the University of Hong Kong.22,53 The primary outcome measure is the immunogenicity by seroconversion rate, defined as the percentage of participants with an HAI antibody titer 10 at baseline and at least a 4fold increase in titer postvaccination on day 21 and day 180. Secondary outcome measures included geometric mean titer (GMT) fold increase in antibody titer. Seroprotection rate was also reported as defined by percentage of participants with HAI antibody titer 40 on day 21 and day 180. We also assessed day 21 immunogenicity of vaccine using the European Committee for Proprietary Medicinal Products (CPMP) guideline: at least one of the following criteria must be met for the viral strain in the vaccine: GMT fold increase 2.5, seroconversion rate >40% and seroprotection rate >70%.54 Safety was evaluated by the presence of adverse effects. A diary was given to the participants to document symptoms of local and systemic adverse events presented within the first 7 days postvaccination. Systemic symptoms included fever (body temperature 37.5 C), headache, malaise, myalgia, and arthralgia; local symptoms included redness, swelling, induration, pain, and ecchymosis, which were documented as solicited events. The diaries were collected upon follow-up on day 21 postvaccination. Based on a previous study of seroconversion rate of 82% for the intradermal seasonal influenza vaccination with a dosage of 3 ug per strain and 70% seroconversion rate for the regular 15 ug hemagglutinin per strain intramuscular vaccination, we calculated that a total sample of 40 participants per group would be needed to demonstrate noninferiority, based on a 2-sided test, type I error rate of 5%, 80% power, and a noninferiority tolerance margin of 1.5.55 The protocol proposed recruiting 50 participants per group to allow for 25% drop out rate. Student t test was used to compare the GMT and GMT folds increases between groups. Noninferiority of the ID vaccine group

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against the IM vaccine group was assessed by the day 21 postvaccination GMT ratio and the seroconversion rates for all 3 strains.56 Noninferiority was defined as the upper limit of the 2-sided 95% confidence interval of the GMT ratio (IM vaccine/ID vaccine) not exceeding 1.5 and the upper limit of the 2-sided 95% confidence interval for the difference in seroconversion rates (IM vaccine minus ID vaccine) not exceeding 10% for all 3 strains.57,58 Continuous variables were expressed as mean  standard deviation. Independent t test was employed to compare the change of continuous variables between 2 different groups. Categorical variables were compared by the c2 test and Fisher exact test. SPSS 18.0 for Windows (SPSS Inc, Chicago, IL) was used for statistical computation. A P value of .05) (Figures 2e5). At day 180, the GMTs, seroconversion rate, seroprotection rate, and GMT fold increase of all 3 strains fell in both groups. However, the GMTs of all 3 strains in ID group were higher than that of IM group, and the difference was significant for H3N2 strain (Figure 6). The seroconversion rate and GMT fold increase of H3N2 strain was significantly higher in the ID group (Table 4). The GMT fold increase of B strain was also significantly higher in the ID group (Table 5). ID vaccination group met more CPMP immunogenicity criteria than IM vaccination group (H1N1 strain: ID group 3 out of 3, IM group 2 out of 3; H3N2 strain and B strain: ID group 2 out of 3, IM group 1 out of 3).

Immunogenicity

Safety

At day 0, GMTs were similar in both vaccine groups. At day 21, noninferiority in immunogenicity (GMT fold increase, seroprotection rate, and seroconversion rate) of the ID group compared with IM

No death or serious adverse event related to vaccination was reported (Table 6). Incidence of systemic adverse events was infrequent, and there was no significant difference for systemic adverse events between ID group and IM group. Incidence of local adverse events, mainly redness and swelling, was significantly more in ID group (P < .01). All local adverse events were mild in severity and resolved in 72 hours.

Results Patient Population

Discussion This study showed that intradermal influenza vaccination (ID vaccination) is noninferior to intramuscular vaccination (IM Table 2 Noninferiority Analysis for Day 21 GMT Ratio and SC Rate Difference Between the 2 Groups (IM vs ID) Vaccine Strain

Victoria (H1N1) California (H1N1) Massachusetts (B)

Fig. 1. Consort diagram outlining study flow. *Intention to treat analysis.

GMT Ratio (IM/ID)

SC Rate Difference (IMeID)

Value

Lower 95% CI

Upper 95% CI

Value

Lower 95% CI

Upper 95% CI

0.60 0.85 0.28

0.47 0.55 0.40

0.65 1.01 1.13

0.06 0.02 e0.04

0.16 0.05 0.14

0.04 0.09 0.06

CI, confidence interval; GMT, geometric mean titer; ID, intradermal (injection of influenza vaccine); IM, intramuscular (injection of influenza vaccine); SC, seroconversion. Noninferiority was defined as the upper limit of the 2-sided 95% CI of the GMT ratio (IM/ID vaccines) not exceeding 1.5 and the upper limit of the 2-sided 95% CI for the difference in seroconversion rates (IM minus ID vaccines) not exceeding 10% for all 3 strains.

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Table 3 Comparison of Immunogenicity of H1N1 Strain (Influenza A/Victoria/361/2011-like Virus) on Day 21 and Day 180 by Hemagglutination-Inhibition (HAI) Between the 2 Groups (IM vs ID) IM

ID

GMT values (95% CI) Day 0 82.0 (50.4e113.6) 77.0 (41.1e114.7) Day 21 265.9 (62.1e469.7) 293.9 (194.9e396.7) Day 180 152.3 (101.5e203.1) 223.2 (96.2e350.2) Day 21 (CPMP criteria)* Seroconversion rate (%) 18 (36) 30 (60) Seroprotection rate (%) 45 (90) 48 (96) 5.2 (2.4e7.9) 8.6 (5.1e12.1) GMT fold increase value (95% CI) Day 180 Seroconversion rate (%) 11 (22) 19 (38) Seroprotection rate (%) 36 (72) 41 (82) GMT fold increase 2.6 (1.8e3.3) 3.8 (2.3e5.3) value (95% CI)

P Value .87 .81 .30 .02y .24 .12

.08 .20 .14

CI, confidence interval; CPMP, Committee for Proprietary Medicinal Products; GMT, geometric mean titer; HAI, hemagglutination-inhibition; ID, intradermal (injection of influenza vaccine); IM, intramuscular (injection of influenza vaccine). *CPMP guideline: at least 1 of the following criteria must be met for the viral strain in the vaccine: GMT fold increase 2.5, seroconversion rate >40% and seroprotection rate >70%. y Significant.

vaccination) in nursing home older adults. Moreover, it showed that immunogenicity of ID vaccination is significantly better than IM vaccination with higher percentage of recipient seroconverted for H1N1 strain and higher day 21 GMT for B strain. Although the immunogenicity of both groups fell on day 180, the noninferior immunogenicity of ID vaccination sustained to day 180. At day 180, the seroconversion rate of H3N2 strain was significantly higher in the ID vaccination group, and GMT fold increase was significantly better in the H3N2 strain and B strain. The ID vaccination group met more CPMP immunogenicity criteria than the IM vaccination group. The noninferiority of ID vaccination compared with IM vaccination has been shown in different studies. In a randomized trial of 257 healthy older adults performed by Chi et al, influenza vaccine by ID route elicited antibody responses similar to IM vaccination. However, superiority of ID against IM vaccination was not shown in this study.59 A possible reason for the different result on superiority is the difference

Table 5 Comparison of Immunogenicity of Influenza B Strain (Influenza B/Massachusetts/2/ 2012-like Virus) on Day 21 and Day 180 by HAI Between the 2 Groups (IM vs ID) IM

ID

P Value

GMT values (95% CI) Day 0 97.8 (68.9e126.7) 87.2 (70.4e104.0) .53 Day 21 146.0 (112.0e180.0) 242.8 (155.2e330.4) .04y Day 180 107.7 (76.1e139.3) 155.2 (118.2e192.2) .053 Day 21 (CPMP criteria)* Seroconversion rate (%) 11 (22) 10 (20) .81 Seroprotection rate (%) 47 (94) 49 (98) .31 GMT fold increase 2.0 (1.6e2.4) 4.9 (1.4e8.4) .09 value (95% CI) Day 180 Seroconversion rate (%) 3 (6) 10 (20) .07 Seroprotection rate (%) 43 (86) 45 (90) .46 GMT fold increase 1.4 (1.0e1.8) 2.4 (1.6e3.2) .03y value (95% CI) CI, confidence interval; CPMP, Committee for Proprietary Medicinal Products; GMT, geometric mean titer; HAI, hemagglutination-inhibition; ID, intradermal (injection of influenza vaccine); IM, intramuscular (injection of influenza vaccine). *CPMP guideline: at least one of the following criteria must be met for the viral strain in the vaccine: GMT fold increase 2.5, seroconversion rate >40% and seroprotection rate >70%. y Significant.

in participants. Although both studies focused on older adults, the study by Chi et al focused on healthy older adults whereas our study focused on frail nursing home older adults with multiple comorbidities, who are more immunocompromised and may have worse immunogenicity to IM vaccination. The better immunogenicity from ID vaccination may be due to abundant immunostimulatory cells, such as dendritic cells and Langerhans cells.60 Direct delivery of

Table 4 Comparison of Immunogenicity of H3N2 Strain (Influenza A/California/7/2009-like Virus) on Day 21 and Day 180 by HAI Between the 2 Groups (IM vs ID) IM

ID

GMT values (95% CI) Day 0 105.8 (84.4e127.2) 101.8 (79.6e124.0) Day 21 191.4 (90.2e292.6) 185.6 (134.2e237.0) Day 180 94.4 (78.1e110.6) 139.2 (105.6e172.8) Day 21 (CPMP criteria)* Seroconversion rate (%) 8 (16) 15 (30) Seroprotection rate (%) 49 (98) 48 (96) GMT fold increase 2.3 (1.0e3.6) 2.7 (1.9e3.5) value (95% CI) Day 180 Seroconversion rate (%) 1 (2) 8 (16) Seroprotection rate (%) 45 (90) 48 (96) 1.2 (0.9e1.5) 2.0 (1.4e2.7) GMT fold increase value (95% CI)

P Value .80 .92 .02y .09 .56 .60

.03y .08 .03y

CI, confidence interval; CPMP, Committee for Proprietary Medicinal Products; GMT, geometric mean titer; HAI, hemagglutination-Inhibition; ID, intradermal (injection of influenza vaccine); IM, intramuscular (injection of influenza vaccine). *CPMP guideline: at least one of the following criteria must be met for the viral strain in the vaccine: GMT fold increase 2.5, seroconversion rate >40% and seroprotection rate >70%. y Significant.

Fig. 2. Day 21 and day 180 geometric mean titer (GMT) by hemagglutination inhibition (HAI) assays.

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Fig. 3. Day 21 and day 180 seroprotection rate by hemagglutination inhibition (HAI) assays.

antigen to immune system cells in the skin by ID vaccination facilitates better immune response in immunocompromised older adults.19 ID vaccination may induce faster and more profound cellular immune responses in the local lymph node than intramuscular vaccination.61 This hypothesis was supported by the 2 different randomized studies performed by Arnou et al and Holland et al.20,62 In both studies, in which the participants were older adults with multiple comorbidities, the geometric mean HAI antibody titers and seroprotection rates were higher with ID vaccination. In another randomized trial of 282 older adults with multiple comorbidities conducted by Hung et al, it also showed that the seroconversion rate, seroprotection rate, and the GMT of the H1N1 strain by HAI were significantly higher in the ID group compared with IM group.57 The seroconversion rate of the H3N2 strain was also significantly higher in the ID group. Results of this study were also consistent with a recent study performed by Morelon et al in immunocompromised organ transplant adults.29 In that study, there was a trend for higher immunogenicity of ID vaccination compared with IM vaccination. Similar observations have also been seen in other vaccines, such as the hepatitis B virus vaccine. A meta-analysis of intradermal hepatitis B virus vaccination in patients with chronic kidney disease showed higher protection rates after intradermal administration of the vaccine than after standard intramuscular vaccinations.63 In this study, the noninferior or even better immunogenicity of ID vaccination sustained to day 180. This result concurred with findings by LerouxRoels et al, which showed that the immunogenicity of intradermal vaccination matched or surpassed those elicited by the reference intramuscular vaccine and persisted up to 1 year after vaccination.24 These findings suggested that ID vaccination is a good alternative to IM vaccination in frail nursing home older adults to induce better immunogenicity. On the other hand, it must be noted that although ID vaccination may have better immunogenicity in nursing home older adults, the immunogenicity, especially the seroconversion rate is still unsatisfactory. Further studies are necessary to compare ID

Fig. 4. Day 21 and day 180 seroconversion rate by hemagglutination inhibition (HAI) assays.

trivalent influenza vaccinaion with other novel influenza vaccination like quadrivalent vaccine to identify the best approach to improve immunogenicity in nursing home older adults. Findings of this study have important public health implications. Nursing home older adults are frail, functionally dependent, immunocompromised, and more vulnerable to complications from influenza infection.3436,38,39 Influenza vaccination in this population is very important. A better immunogenicity by ID vaccination may imply a better efficacy with less influenza infection and related complication. Moreover, ID vaccination is advantageous from a safety point of view. As the needle penetrates only 1.5 mm into the skin, the risk of damage to nerves and blood vessels in frail and thin older adults is minimized with the IM vaccination. ID vaccination also prevents risk of severe hematoma formation because of IM vaccination in patients having anticoagulation. With traditional techniques, reliable intradermal vaccination requires special training of the administrator.64 However, with the easy-to-use intradermal microinjection system employed in this study, it ensures a reliable and reproducible intradermal injection. All these factors may contribute to increase vaccine uptake in this population.65 In this study, there were more local adverse events in the ID vaccination group. This finding concurred with most studies of ID vaccination. The increase in local adverse events is linked to the underlying immunological response in the skin, which is more visible with ID than IM vaccination. However, as demonstrated in this study and many other studies, those local adverse events are mild and without long-term sequelae. More importantly, these reactions were not associated with increased incidence of injection site pain. 42 Studies by Eizenberg et al and Arnou et al showed that even though ID vaccination recipients are associated with more local

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Fig. 5. Geometric mean titer (GMT) fold increase on day 21 and day 180.

adverse events, it still is well accepted among recipients.30,33 It may be due to the small needle size and high immunogenicity. On the other hand, presence of local adverse events was shown to correlate well with subsequent immunogenicity and may be used as a marker for effective ID vaccination.21,57 A major strength of this study is the comprehensive inclusion of frailty assessment using CSHA clinical frailty scale and CHS phenotypic definition, comorbidity assessment using Charlson comorbidity index and nutritional assessment using body mass index and albumin level. Immunogenicity and efficacy of influenza vaccination may be affected by these factors.6669 To our knowledge, this is the first randomized study assessing immunogenicity of influenza vaccination in older adults with comprehensive consideration of these factors. With inclusion of these assessments, it allows better characterization of older adults included in this study. The participants were frail with mean frailty index by CSHA clinical frailty scale 2, mean frailty index by CHS phenotypic definition 4, and had multiple comorbidities with mean Charlson comorbidity index 2. It allows generalization of study results to most nursing home older adults. There were several limitations in this study. Among 703 nursing home older adults assessed for eligibility, 363 of them did not fulfill inclusion criteria. Many of them were excluded because of the presence of cognitive impairment. It prevented them from understanding the information of the study, and hence, they were unable to make informed consent. This is an unavoidable situation for intervention trial in nursing home older adults, and we reckoned that it might affect the generalizability of the results.70,71 However, we tried to compensate this limitation by inclusion of frailty assessment. The mean frailty index by CSHA clinical frailty scale was 2, and the mean frailty index by CHS phenotypic definition was 4 for the participants,

Fig. 6. Geometric mean titer (GMT) by hemagglutination inhibition (HAI) assays of different strains by different vaccination methods [intradermal (IM) vs intramuscular (IM)]. *Significant difference in geometric mean titer between IM and ID vaccination.

suggesting that many participants were frail, and the result should generalize to most nursing home older adults. Another limitation is that the participants were not blinded to the route of vaccination, and we did not use objective assessment for the localized reaction to vaccination. It may affect the reporting of adverse events but would not have affected the objective immunogenicity outcomes. Besides, many participants had high day 0 GMT, and it may be due to the high influenza vaccination rate in the preceding year. However, there was no significant difference for GMT between groups. It should not affect the observation that ID vaccination induced more seroconversion than IM vaccination. In conclusion, this randomized controlled trial suggested that intradermal vaccination of influenza vaccine is noninferior to intramuscular vaccination in nursing home older adults. Furthermore, ID

T.-C. Chan et al. / JAMDA 15 (2014) 607.e5e607.e12 Table 6 Incidence of Local and Systemic Adverse Events 17. Local Swelling Redness Induration Ecchymosis Pain Systemic Fever* Headache Malaise Myalgia Arthralgia

IM

ID

P Value

1 2 0 0 3

10 13 0 0 2

.004y .002y NA NA 1.0

2 3 4 3 2

1 3 6 5 4

18. 19. 20.

21. 1.0 1.0 .74 .72 .68

ID, intradermal (injection of influenza vaccine); IM, intramuscular (injection of influenza vaccine); NA, not available. *Body temperature 37.5 C. y Significant.

22.

23. 24.

25.

vaccination is superior in some components of the immunogenicity assessment without compromising safety. The noninferior or even superior immunogenicity was sustained to 6 months. These findings suggested that ID vaccination is a good alternative to IM vaccination in frail nursing home older adults to induce better immunogenicity against influenza. Acknowledgments The authors gratefully acknowledge the Young Investigator Research Fund of Hong Kong College of Physician, which partially supported this project financially. References 1. Fleming DM, Elliot AJ. The impact of influenza on the health and health care utilization of elderly people. Vaccine 2005;23:51e559. 2. Pitman RJ, Melegaro A, Gelb D, et al. Assessing the burden of influenza and other respiratory infections in England and Wales. J infect 2007;54:530e538. 3. World Health Organization. Influenza vaccines. WHO position paper. Wkly Epidemiol Rec 2005;80:277e287. 4. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. J Am Med Assoc 2003; 289:179e186. 5. Chan TC, Hung IFN, Luk JKH, et al. Efficacy of trivalent seasonal influenza vaccination on mortality and hospitalization in Chinese nursing home older adults. J Am Med Dir Assoc 2013;14:889e894. 6. Chan TC, Hung IFN, Luk JKH, et al. Effectiveness of influenza vaccination in institutionalized older adults: A systematic review. J Am Med Dir Assoc 2013; 15:226.e1e226.e6. 7. Chan TC, Hung IFN, Luk JKH, et al. Efficacy of dual vaccination of pandemic H1N1 2009 influenza and seasonal influenza on institutionalized elderly: A one-year prospective cohort study. Vaccine 2011;29:7773e7778. 8. Jefferson T, Rivetti D, Rivetti A, et al. Efficacy and effectiveness of influenza vaccines in elderly people: A systematic review. Lancet 2005;366:1165e1174. 9. Simansen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: An ongoing controversy. Lancet Infect Dis 2007;7: 658e666. 10. Grubeck-Loebenstein B, Della Bella S, Iorio AM, et al. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 2009;21:201e209. 11. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: A quantitative review. Vaccine 2006;24:1159e1169. 12. Loebermann M1, Voss U, Meyer S, et al. Clinical trial to evaluate the safety and immunogenicity of a trivalent surface antigen seasonal influenza vaccine produced in mammalian cell culture and administered to young and elderly adults with and without A(H1N1) pre-vaccination. PloS One 2013;8:e70866. 13. Guy B. The perfect mix: Recent progress in adjuvant research. Nat Rev Microbiol 2007;5:505e517. 14. O Hagan DT. MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection. Expert Rev Vaccines 2007;6:699e710. 15. Falsey AR, Treanor JJ, Tornieporth N, et al. Randomized double-blind controlled phase 3 trial comparing the immunogenicity of high dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 2009;200: 172e180. 16. Palache AM, Beyer WE, Sprenger MJ, et al. Antibody response after influenza immunization with various vaccine doses: A double-blind placebo-controlled,

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Immunogenicity and safety of intradermal trivalent influenza vaccination in nursing home older adults: a randomized controlled trial.

To compare the immunogenicity and safety between full-dose (15 μg) intramuscular (i.m.) and full-dose (15 μg) intradermal (i.d.) immunization of the t...
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