Original Clinical Science

Influenza Vaccine Antibody Response and 6-month Persistence in Lung Transplant Recipients Using Two Definitions of Seroprotection Andrew J. Long, Sara L. Worzella, John J.M. Moran, and Mary S. Hayney Background. Lung transplant recipients are among those with the highest risk of influenza infection and complications each year. A few studies show adequate responses after influenza immunization; no studies examined the season-long protection. Methods. Influenza antibody concentrations were measured using hemagglutination inhibition assays before immunization, 2 to 4 weeks after immunization, and 6 months after immunization in 25 healthy controls and 54 lung transplant patients. Two definitions of seroprotection (40 hemagglutination units (HAU) and 160 HAU which confers about 95% protection) were used. Results. Influenza vaccine responses were high in both groups postimmunization (100% at 40 HAU and 60% healthy and 61% lung transplant at 160 HAU; P = 1.0; chi-square). At 6 months after immunization, seroprotection rates at 40 HAU (95% healthy and 97% lung transplant; P = 1.0) and at 160 HAU (24% healthy and 36% lung transplant; P = 0.40) were observed. Conclusion. Seroprotection rates do not differ between healthy and transplant groups over 6 months when 40 HAU or 160 HAU is used. However, the seroprotection rates are disappointingly low when 160 HAU (the antibody concentration associated with 95% protection from infection) is used. Annual influenza vaccine should continue to be a high priority for lung transplant patients.

(Transplantation 2015;99: 885–889)

A

lthough influenza virus infections are a serious public health concern within the general population, lung transplant recipients are among those with the highest risk of influenza infection and influenza-associated complications because of continuous, medication-induced immunosuppression combined with physiologic changes occurring in the lungs, the primary site of influenza infection.1-8 Some of the physiologic changes that are noted in lung transplant patients include high degree of immunosuppression, altered mucociliary clearance, repeated airway instrumentation, bronchial anastomotic obstruction, disruption of lymphatic drainage, and the exposure of the transplanted organ to the environment.9

Received 7 April 2014. Revision requested 8 May 2014. Accepted 8 July 2014. University of Wisconsin School of Pharmacy 777 Highland Avenue, Madison, WI. Mr. Long, Ms. Worzella, and Mr. Moran have no conflicts of interest to disclose. Dr. Hayney is a member of speakers’ bureau for Merck Vaccines. NATCO Research Grant Award partially supported this work. The remaining funding was from the University of Wisconsin-Madison School of Pharmacy. A.J.L. participated in research design, data analysis, and writing of the article. S.L.W. participated in writing the article. J.J.M.M. participated in performance of the research and data analysis. M.S.H. participated in research design, writing the article, performance of the research, data analysis. ClinicalTrials.gov registry number: NCT00205270 Correspondence: Mary S. Hayney, PharmD, MPH, FCCP, BCPS, University of Wisconsin School of Pharmacy, 777 Highland Avenue, Madison, WI. ([email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9904-885 DOI: 10.1097/TP.0000000000000391

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Given the significant risk of morbidity and mortality, it is critical and highly recommended that lung transplant patients receive annual influenza immunizations that confer protection throughout the influenza season. Previous studies have demonstrated that transplant recipients and nonimmunocompromised populations display similar rates of seroprotection between 3 and 5 weeks after influenza vaccination, despite the transplant population achieving generally lower antibody concentrations.10-12 Two studies show influenza vaccine antibody persistence at reasonable rates at 1 year, but not 2 years, after immunization.13,14 However, there are no studies comparing seroprotection rates 6 months after vaccination, reflecting adequate coverage throughout the entire influenza season. Seroprotection has traditionally been defined as an antibody concentration of at least 40 hemagglutination units (HAU) after vaccination, which is the criterion for influenza vaccine licensure.15 This concentration of antibody provides protection from infection at a rate of about 50% in typically healthy individuals.16,17 Protection from infection improves with higher antibody concentrations.16-19 For this study, a HAU of at least 160 was selected as a more conservative definition of seroprotection, where protection may reach up to 95%.16,18,20 Our hypothesis is that seroprotection, defined as 40 HAU or greater, will persist up to 6 months at high rates in lung transplant patients and that these rates will be comparable to the rates in healthy individuals. As a secondary outcome, we also compared seroprotection rates when 160 HAU or greater was used to define seroprotection. RESULTS The number of participants lost to follow-up and excluded from 6-month analyses because of serologic evidence of www.transplantjournal.com

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FIGURE 1. Tracking participants enrolled in the study. n1 = participants with 4-week data for all three vaccines viruses; n2 = participants with no response (≥40 hemagglutination units (HAU)) to any one of the three vaccine viruses after vaccination; n3 = participants with a serologic response (≥40 HAU) to any of the three vaccine virus after vaccination for whom we obtained data at 6 months; n4 = participants with a serologic response (≥40 HAU) after vaccination for whom we did not obtain a 6-month data; n5 = participants with evidence of influenza infection to one or more influenza vaccine viruses (increase in titer concentrations by two dilutions between postvaccination and 6 months). HAU, hemagglutination units.

influenza infection can be found in Figure 1. The transplant patients were statistically significantly older than the healthy patients. There was no difference in the male to female ratio between groups (Table 1). The mean time because transplant and immunosuppressive medication regimen data are reported. Other than significantly different pre-H3N2 and 6-month B concentrations between the groups (Figure 2) and a significantly greater proportion of healthy patients achieving seroconversion to the H3N2 vaccine virus, there were no significant differences in seroprotection rates between healthy and lung transplant participants after immunization and 6 months after vaccination, regardless of whether seroprotection was defined as an antibody concentration of at least 40 or 160 HAU (Table 2). There were also no differences in the proportions of healthy and transplant participants who achieved seroprotection to at least one, two, or all three vaccine viruses after immunization and at

6 months. Again, these results did not vary based on which HAU cutoff value for seroprotection was used (Table 2). Decline in antibody concentrations to each vaccine virus between the postvaccination and 6-month timepoint was calculated in healthy and transplant participants and in all participants combined. The decline in each group was significant for each vaccine virus, except for H1N1 and B antibody concentrations in the healthy population and transplant population, respectively; however, the magnitude of the decline in titer concentrations between postvaccination and 6-month measurement did not significantly differ between healthy and lung transplant participants (Figure 3). Although participants with serologic evidence of influenza infection were excluded from the 6-month analyses, the antibody data to other vaccine viruses were collected. Two

TABLE 1.

Participant demographics Healthy

Age, yr (mean ± SD) Male sex (%) Time since transplant, mo (mean, range) Transplant medications Azathioprine Cyclosporine Mycophenolate Sirolimus Tacrolimus a

t test. Chi-square test.

b

49.0 ± 10.8 10/25 (40%) — — — — — —

Lung transplant

56.3 ± 11.5 25/54 (46%) 76.9 (5–201)

6/54 (11%) 21/54 (39%) 41/54 (76%) 6/54 (11%) 33/54 (61%)

P

0.009a 0.635b — — — — — —

FIGURE 2. Bar graph showing mean antibody concentrations in each group for each vaccine virus up to 6 months. Healthy controls had lower preimmunization mean H3N2 antibody concentrations than lung transplant patients (P = 0.003; t test), and healthy individuals had lower antibody concentrations at 6 months post immunization to influenza B virus than lung transplant patients (P = 0.03; t test). No differences were found with the other between group comparisons.

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TABLE 2.

Antibody responses after influenza immunization Healthy

Transplant

Pa

Sample size (4 weeks) 25 54 — Sample size (6 mo) 21 39 — Seroconversion (4-fold increase in antibody titer between pre and post) H1N1 10/25 (40%) 13/49 (27%) 0.292 H3N2 20/25 (80%) 20/49 (41%) 0.002 B 7/25 (28%) 8/49 (16%) 0.359 Seroprotection (4-week antibody titer ≥1:40) H1N1 23/25 (92%) 51/54 (94%) 0.649 H3N2 24/25 (96%) 48/54 (89%) 0.422 B 18/25 (72%) 44/54 (81%) 0.384 Seroprotection (6-mo antibody titer ≥1:40) H1N1 15/21 (71%) 31/39 (79%) 0.532 H3N2 20/21 (95%) 29/39 (74%) 0.078 B 9/21 (43%) 24/39 (62%) 0.186 Seroprotection (4-week antibody titer ≥1:160) H1N1 5/25 (20%) 13/54 (24%) 0.779 H3N2 12/25 (48%) 26/54 (48%) 1.000 B 2/25 (8%) 8/54 (15%) 0.490 Seroprotection (6-mo antibody titer ≥1:160) H1N1 1/21 (5%) 3/39 (8%) 1.000 H3N2 5/21 (24%) 8/39 (21%) 0.755 B 0/21 (0%) 4/39 (10%) 0.287 Seroprotection to vaccine viruses (4-week antibody titer ≥1:40) At least one 25/25 (100%) 54/54 (100%) — At least two 23/25 (92%) 50/54 (93%) 1.000 Three 17/25 (68%) 39/54(72%) 0.792 Seroprotection to vaccine viruses (6-mo antibody titer ≥1:40) At least one 20/21 (95%) 38/39 (97%) 1.000 At least two 17/21 (81%) 30/39 (77%) 1.000 Three 7/21 (33%) 16/39 (41%) 0.592 Seroprotection to vaccine viruses (4-week antibody titer ≥1:160) At least one 15/25 (60%) 33/54 (61%) 1.000 At least two 4/25 (16%) 13/54 (24%) 0.560 Three 0/25 (0%) 1/54 (2%) 1.000 Seroprotection to vaccine viruses (6-mo antibody titer ≥1:160) At least one 5/21 (24%) 14/39 (36%) 0.395 At least two 1/21 (5%) 1/39 (3%) 1.000 Three 0/21 (0%) 0/39 (0%) — a

Chi-square test.

healthy and four transplant participants had serologic evidence of influenza infection at the 6-month measurement. Of the six subjects with serologic evidence of infection, four had evidence of H1N1, one had evidence of H3N2, and three had evidence of B infections. Of the four participants with H1N1 infection, two and four individuals had seroprotection (≥40 HAU) to H3N2 and B, respectively, at 6 months. The one patient with evidence of H3N2 demonstrated seroprotection to B at 6 months. All three individuals with evidence of infection with influenza B demonstrated seroprotection to H1N1 and H3N2 at 6 months. On analysis, age was generally found to be significantly negatively correlated with antibody response at 6 months in our population, but not immediately after vaccine administration. The observed decline in antibody with age was statistically significant for H1N1 (Pearson correlation,

887

−0.270; P = 0.029) and H3N2 (Pearson correlation, −0.363; P = 0.003), but not for influenza B (Pearson correlation, −0.209; P = 0.076), and only apparent when the entire study cohort was analyzed as a whole. DISCUSSION Postvaccination seroprotection rates to the three vaccine viruses were high and persisted at high rates throughout the 6 months when an antibody concentration of at least 40 HAU was used to define protection. Although the decline in antibody concentration within each population was found to be statistically significant for almost all vaccine viruses over the 6-month period, seroprotection still persisted at high rates at the 6-month timepoint with no difference between healthy and immunosuppressed lung transplant participants. H1N1 and B antibody concentrations did not appear to decline significantly in the healthy and transplant populations, respectively, likely because of insufficient power to identify such minor changes in the smaller groups. When the decline in all participants combined was assessed, the antibody concentrations toward each of the three strains declined significantly over the course of the season. When changes in concentrations between postvaccination and 6-month measurements were compared between the groups, there were no differences between the healthy and transplant participants, suggesting that the transplant population is capable of mounting and maintaining antibody concentrations as well as the healthy population over the course of a typical 6-month influenza season. Of note, the specific viral strain included in the vaccine seemed to influence antibody persistence more than the immune status of the individual. Seroprotection rates were highest for H3N2 and lowest toward B in both groups. These results are similar to previous studies demonstrating that antibody levels toward influenza B virus are least persistent after vaccination compared to H1N1 and H3N2.14,21,22 Although seroprotection rates were high within both groups in the first set of analyses, these rates were based on the 40 HAU criterion, which is the benchmark used for vaccine licensure.15 However, a second set of analyses was performed using antibody titers of at least 160 HAU as the basis for protection for about 95% of those immunized.16,18,20 The seroprotection rates were still no different at the postvaccination and 6-month timepoints between groups; however, both groups had far lower rates of seroprotection, especially at 6 months. These findings support the need for continued focus on researching strategies to improve antibody responses in both healthy and immunosuppressed individuals. One method may be the high dose influenza vaccine. However, additional research is needed to determine whether this would be a viable strategy for significantly increasing seroprotection rates in immunocompromised individuals. All participants received the influenza vaccine in the prior season, but all three influenza viruses included in the vaccine changed from the previous season. Interestingly, the healthy individuals had lower H3N2 antibody concentrations preimmunization than the lung transplant patients and, therefore, higher rates of seroconversion. Healthy individuals may have less experience with influenza vaccines, in general, than those with severe respiratory conditions. An

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FIGURE 3. Antibody waning from post-immunization to 6 months. Antibody concentrations to each virus for healthy (black symbols) and lung transplant participants (open symbols) are shown as they decline over the course of the season. No significant differences in the magnitude of decline were observed between the groups. However, a statistically significant decline in the postimmunization to 6-month antibody concentrations was found for all comparisons except the healthy group for H1N1 and transplant group for influenza B.

immunologically naive host is more likely to mount a large change in antibody concentration and increase the likelihood of seroconversion.23 Seroconversion rates after influenza vaccine are often reported as a measure of vaccine response, but their clinical significance is not known.15 A previous study in lung transplant patients showed a decreased rate of seroconversion or the ability to mount a vigorous immune response to a new influenza vaccine virus.11 However, a second study failed to demonstrate a similar phenomenon.10 Even this study shows differing results with the three vaccine viruses. Our study has several limitations. Studies showing decreased antibody response to influenza vaccine include individuals much older than 65 years.22,24,25 In this study, the mean age of the transplant group was significantly greater than that of the healthy group, with 16 individuals in the transplant population and one in the healthy group over the age of 65 years. Age was negatively correlated with influenza antibody concentrations which should skew the results in favor of the healthy population. However, we found few differences in antibody concentrations or responses rates between the groups. Data are currently lacking with regard to the antibody concentration that confers protection in immunocompromised individuals, and this concentration may differ from that needed in healthy subjects. For this reason, we performed seroprotection analyses using both the 40 and 160 HAU values as benchmarks for seroprotection to examine a wider range of concentrations with a goal of increasing clinical relevance; however, because these values are only supported by evidence from nonimmunocompromised populations, specific research is required to establish antibody concentrations needed for protection in the immunocompromised population. Additionally, because our study only examines one specific season of influenza vaccine in one type of immunocompromised subject, it is challenging to generalize our findings to all vaccines used in all types of immunocompromised individuals or even future influenza vaccines. Using the serologic diagnosis of influenza infection allowed us to detect unreported and undiagnosed influenza infections and is useful for a study of influenza vaccine antibody persistence where waning of antibody concentrations can affect the main outcome. Influenza infections may have

been missed if they did not cause a large enough increase in relevant influenza antibody concentrations. Clinical diagnoses of influenza will not have an effect on the study outcome because it may have been caused by an influenza strain not contained in the vaccine. As hypothesized, seroprotection rates are high and persist at acceptable rates over 6 months when 40 HAU is used to define protection. These rates do not differ between healthy and transplant groups. This suggests that immune status may be irrelevant in an individual’s ability to mount and maintain antibody responses after influenza vaccination for the duration of a typical 6-month influenza season. The recent recommendation to begin influenza vaccine administration when vaccine becomes available26 should have little effect on the protection conferred to lung transplant patients because our results show good persistence of antibody over at least 6 months. However, seroprotection rates were equally unimpressive in both study groups when the more conservative 160 HAU criterion for protection was used, especially at 6 months, stressing the need for additional research regarding strategies to improve antibody responses regardless of immune status. In addition to the low 6-month seroprotection rates when a more conservative definition of protection was used, our findings support the recommendation to provide annual influenza immunization to lung transplant recipients based on their ability to mount immune responses comparable to that of healthy individuals for a full 6-month period. Both healthy and immunosuppressed individuals should receive influenza vaccines annually to minimize influenza-associated morbidity and mortality by achieving and maintaining the highest rates of seroprotection possible. MATERIALS AND METHODS Participants

We compared influenza vaccine responses in lung transplant patients and healthy control subjects without lung disease over the course of the 2008 to 2009 influenza season. Fifty-four lung transplant subjects were recruited from the University of Wisconsin lung transplant clinic. All lung

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transplant patients were maintained on immunosuppressive regimens consisting prednisone, a calcineurin inhibitor, and an antiproliferative agent. Twenty-five healthy individuals without lung disease were recruited from a pool of health care workers at the University of Wisconsin Hospitals and Clinics or from the community. The study protocol was approved by the University of Wisconsin Health Sciences Institutional Review Board for Human Investigation (protocol 2009–0002), and all participants gave written informed consent (ClinicalTrials.gov registry number: NCT00205270). Protocols and Procedures

All participants received a single intramuscular dose of the 2008–2009 seasonal trivalent inactivated influenza vaccine in October or early November. Serum was collected from participants before immunization, 2 to 4 weeks after immunization (postimmunization), and 6 months after immunization. Serum was stored at −80°C until influenza antibody to A/Brisbane/59/2007(H1N1)-like, A/Brisbane/10/2007(H3N2)like, and B/Florida/4/2006-like was measured using hemagglutination inhibition assays.27 The laboratory staff performing hemagglutination inhibition assay using standard microtiter techniques was blinded to participant status. Antibody concentrations that were below the lower limit of detection (

Influenza vaccine antibody response and 6-month persistence in lung transplant recipients using two definitions of seroprotection.

Lung transplant recipients are among those with the highest risk of influenza infection and complications each year. A few studies show adequate respo...
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