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Vaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy older people

Vaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy... www.nature.com/npjvaccines ARTICLE OPEN Vaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy older people 1 2 3 2 4,6 5 1 Natale Snape , Gary P. Anderson , Louis B. Irving , Andrew G. Jarnicki , Aeron C. Hurt , Tina Collins , Yang Xi and 1,5 John W. Upham Though clinical guidelines recommend influenza vaccination for chronic obstructive pulmonary disease (COPD) patients and other high-risk populations, it is unclear whether current vaccination strategies induce optimal antibody responses. This study aimed to identify key variables associated with strain-specific antibody responses in COPD patients and healthy older people. 76 COPD and 72 healthy participants were recruited from two Australian centres and inoculated with influenza vaccine. Serum strain-specific antibody titres were measured pre- and post-inoculation. Seroconversion rate was the primary endpoint. Antibody responses varied between vaccine strains. The highest rates of seroconversion were seen with novel strains (36–55%), with lesser responses to strains included in the vaccine in more than one consecutive year (27–33%). Vaccine responses were similar in COPD patients and healthy participants. Vaccine strain, hypertension and latitude were independent predictors of seroconversion. Our findings reassure that influenza vaccination is equally immunogenic in COPD patients and healthy older people; however, there is room for improvement. There may be a need to personalise the yearly influenza vaccine, including consideration of pre-existing antibody titres, in order to target gaps in individual antibody repertoires and improve protection. npj Vaccines (2022) 7:8 ; https://doi.org/10.1038/s41541-021-00422-4 INTRODUCTION this study showed that influenza vaccination reduced COPD exacerbations relative to placebo, it is notable that the active Chronic obstructive pulmonary disease (COPD) is a common, serious intervention group received double the recommended vaccine lung disease caused by smoking and exposure to air pollutants . dose . In contrast, we previously reported that the humoral COPD is the third leading cause of mortality worldwide with the immune response to influenza vaccination may be sub-optimal in global disease burden likely to increase substantially in coming 3,4 COPD . There is considerable lack of knowledge regarding the years . Common respiratory viruses such as rhinoviruses and 5,6 immune response to influenza vaccine in COPD patients— influenza often trigger COPD exacerbations ,and can lead to whether the current vaccine strategy is sufficiently immunogenic secondary bacterial infections, hospitalisations and death . Clinical and whether subgroups of patients fail to mount a robust guidelines recommend influenza vaccination as a priority for COPD antibody response. Addressing these knowledge gaps is necessary patients and other high-risk populations including the elderly and for developing better vaccine strategies for COPD patients and immune compromised . However, vaccine efficacy may be sub- other at-risk populations. optimal in these high-risk populations, either because of age-related 9–12 The aim of this study was to examine vaccine immunogenicity immune dysfunction known as immunosenescence ,orbecause 13,14 in COPD patients and age-matched healthy older people, in order of disease-specificdeficits in anti-viral immunity . to identify key variables associated with strain-specific antibody Vaccines act by inducing antibody production and long-lived responses. The primary study endpoint was seroconversion, memory B cells, however, influenza vaccine efficacy can be less 15 defined as ≥four-fold increase in haemagglutination inhibition than ideal . Post-vaccination, influenza antibody titres decline 16,17 (HI) antibody titre at 28 days post-inoculation (p.i.). Seroprotection, relatively quickly, particularly in the elderly , so annual (defined by the World Health Organisation (WHO) as an HI vaccination is required. Additionally, the influenza virus haemag- antibody titre ≥1:40) was a secondary endpoint. Notably, this glutinin (HA) and neuramidase surface proteins exhibit a high 18 study was not designed to assess whether vaccination reduces the propensity for antigenic drift and evasion of host antibodies ,so incidence of influenza infections or COPD exacerbations. vaccine formulations require updating annually. Strain selection for the vaccine each year is usually based on knowledge of strains circulating in the opposite hemisphere’s winter . RESULTS Recent systematic reviews have concluded that influenza vaccination is probably beneficial in COPD, though evidence gaps Influenza vaccine formulations were based on Australian Govern- remain , with relatively few randomised controlled trials (RCTs) ment recommendations and differed slightly across the study years directly assessing whether influenza vaccination reduces COPD 2015-2017 (Table 1). The H1N1_A/CALIFORNIA/07/2009-like and exacerbations . The largest RCT in the last 50 years was B_PHUKET/3073/2013-like strains were components in the approved conducted in predominantly vaccine naïve participants. Though vaccine formulation in all three years of this study, enabling greater 1 2 Faculty of Medicine, The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD, Australia. Lung Health Research Centre, Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, Australia. Department of Respiratory Medicine, The Royal Melbourne Hospital, Parkville, VIC, Australia. WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute 5 6 for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia. Metro South Health, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. Present address: Department of Infectious Diseases, Roche Pharma Research & Early Development, Basel, Switzerland. email: john_upham@health.qld.gov.au Published in partnership with the Sealy Institute for Vaccine Sciences 1234567890():,; N. Snape et al. Table 1. WHO-recommended southern-hemisphere influenza vaccine formulations for trivalent and quadrivalent vaccines for each vaccine year. 2015 2016 2017 H1N1_A/CALIFORNIA/07/2009-like H1N1_A/CALIFORNIA/07/2009-like H1N1_A/CALIFORNIA/07/2009-like B/PHUKET/3073/2013-like B/PHUKET/3073/2013-like B/PHUKET/3073/2013-like B/BRISBANE/60/2008-like B/BRISBANE/60/2008-like H3N2_A/SWITZERLAND/ 9715293/2013-like H3N2_A/HONG KONG/4801/2014-like H1N1_A/MICHIGAN/45/2015-like Table 2. Demographics and clinical characteristics of the study population: Comparative between COPD and older healthy participants. Demographic and Clinical Characteristics Total COPD Healthy p value (COPD vs healthy) N 147 75 72 ns Female—n (%) 60 (40.8) 23 (30.6) 37 (51.4) 0.01 Male—n (%) 87 (59.2) 52 (69.3) 35 (48.6) 0.01 Brisbane cohort 94 48 46 ns Melbourne cohort 53 27 26 ns 2016 returns from 2015 (%) 9 (6) 4 (5.3) 5 (6.9) 2017 returns from 2016 (%) 9 (6) 5 (6.6) 4 (5.5) Age (95% CI) Mean 66.8 (65.3–68.3) 68.7 (66.7–70.7) 64.9 (62.7–67.1) <0.01 Median 67 (64–69) 69 (67–71) 63 (60–68) Range 50–90 51–90 50–88 BMI (95% CI) Mean 28.1 (27.0–29.2) 28.3 (26.6–30.0) 27.9 (26.6–29.1) ns Median 26.7 (26.1–27.7) 26.6 (24.9–28.0) 26.9 (26.1–28.3) Range 18.2–52.9 18.2–52.9 19.0–44.4 Smoking status n (%) Never 40 (27.2) 5 (6.6) 35 (48.6) <0.0001 Former 84 (57.1) 49 (65.3) 35 (48.6) ns Current 23 (15.6) 21 (28) 2 (2.8) <0.0001 Pack Years (95% CI) Mean 31.3 (25.6–37.1) 51.6 (43.5–59.7) 10.2 (5.6–14.7) <0.0001 Median 21.0 (14.0–30.0) 44.5 (39.0–53.0) 0 (0–3) Range 0–168 0–168 0–76 Diabetes—n (%) 20 (13.6) 12 (16) 8 (11.1) ns Heart condition—n (%) 35 (23.8) 23 (30.6) 12 (16.7) ns Asthma—n (%) 23 (15.6) 18 (24) 5 (6.9) <0.01 Bronchiectasis—n (%) 6 (4.1) 6 (8) 0 <0.05 High blood pressue—n (%) 57 (38.8) 33 (44) 24 (33.3) ns High cholesterol—n (%) 52 (35.4) 27 (36) 25 (34.7) ns Mean FEV predicted % (95% CI) 74.0 (68.6–79.5) 48.7 (43.3–52.0) 102.7 (98.4–107) <0.0001 Mean FEV /FVC % (95% CI) 62.6 (59.1–66) 50.1 (45.4–54.9) 76.0 (73.8–78.3) <0.0001 Vaccine history n (%) Never 5 (3.4) 3 (4) 2 (2.8) ns Previous 2 years (both) 120 (81.6) 63 (84) 57 (79.2) ns Previous year (only) 11 (7.5) 7 (9.3) 4 (5.5) ns Year before previous (only) 4 (2.7) 1 (1.3) 3 (4.2) ns Ever before (except previous 2 years) 7 (4.8) 1 (1.3) 6 (8.3) ns Significance (p values) calculated by Welch’s t test (means) and Yates’ Chi-square test (proportions). ns not significant. statistical power in assessing responses to these strains. A Participant characteristics quadrivalent vaccine formulation in 2016 and 2017 added a second Participant demographics are shown in Table 2. The mean age of B strain (Brisbane/60/2008-like) to the previous trivalent vaccine. COPD participants was 3.8 years higher than that of healthy One strain differed each year, usually an H3N2 or H1N1 strain. participants (p < 0.01), and just under 70% of COPD participants npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences 1234567890():,; N. Snape et al. H1N1_California 0.80 B_Phuket ** B_Brisbane 0.70 4096 # H3N2_HongKong 0.60 H3N2_Switzerland H1H1_Michigan 0.50 0.40 0.30 0.20 0.10 0.00 0 28 0 28 0 28 0 28 0 28 0 28 Days post vaccine Fig. 2 Antibody response pre- (D0) and post- (D28) vaccine for each strain. Data is expressed as GMT ± 95% confidence intervals. Temporal differences for each strain are considered significant if confidence intervals (CI) do not overlap. Dotted horizontal line represents a GMT of 1:40, indicative of seroprotection. GMT: geometric mean titre. Fig. 1 Proportion of subjects that seroconverted (≥ 4-fold rise in Ab titre from D0). Data displayed as proportion ± standard error of demonstrating seroprotection. The high pre-vaccine GMT, seen fit. Red bars: recurring strains (present in vaccine ≥2 seasons), blue in both B strains and the novel strain H3N2/Hong Kong, indicates bars: novel strains in vaccine season. **significant difference (p < that our cohort already exhibited strain-specific seroprotection 0.001) to all recurring strains (H1N1/California, B/Phuket & B/ prior to vaccination. Interestingly, the two novel H3N2 vaccine Brisbane), significant difference (p < 0.05) to recurring strain H1N1/California only. Significance between proportions calculated strains (H3N2/Hong Kong & H3N2/Switzerland) induced greater by Yates’ Chi-square test. degrees of post-vaccine seroprotection, with H3N2/Hong Kong also eliciting a higher GMT, than the recurring strains (Fig. 2), were male, whereas the healthy participants comprised similar signifying that these two novel vaccine strains were particularly numbers of females and males. Compared with healthy partici- efficacious. pants, COPD patients had significantly greater cumulative smoke exposure (pack years), were more likely to be current smokers, and Comparative seroconversion and seroprotection rates more likely to report physician-diagnosed comorbidities, such as Antibody responses to the various vaccine strains were broadly asthma and bronchiectasis. Over 90% of our study population similar in the COPD and healthy participants. Few differences are received an influenza vaccine in at least one of the two years prior observed between COPD and healthy participants in either pre- or to enrolment. Population demographics were analogous across post-vaccine seroprotection, or in GMT (Table 3). Vaccine strain B/ the Brisbane and Melbourne study sites (Supplementary Table 1). Phuket elicited a significantly higher seroconversion rate in COPD Nine subjects participated in the study in consecutive years patients than in healthy participants (adjusted OR p = 0.038), and (2015 and 2016), and another nine participated in both 2016 and COPD patients had higher pre- and post-vaccine GMT to vaccine 2017. No subjects participated in three consecutive years. Because strain A/Hong Kong than healthy participants. These differences the influenza vaccine formulation varies by year and because were not seen with the other strains. clinical characteristics may fluctuate over time, these ‘repeat We further assessed whether strain-specific antibody responses participants’ were analysed as individual subjects within each varied by study location (Supplementary Table 2). Melbourne participating year. participants tended to have higher post-vaccine seroprotection rates and GMT than Brisbane participants, though differences Vaccine-induced antibody response vary by strain were only significant for the H1N1/California strain (p = 0.03, adjOR p = 0.029 and GMT p ≤ 0.001). The H1N1/California strain We compared day 28 p.i. seroconversion rates for those strains also elicited a significantly higher seroconversion rate (p = 0.19, included in the vaccine formulation in more than one consecutive adjOR p = 0.012) in Melbourne relative to Brisbane participants. year (hereafter referred to as ‘recurring strains’), contrasting this Melbourne participants also had higher pre-vaccine seroprotec- with vaccine strains that were ‘novel’ to a vaccine season (Fig. 1). tion rates for the P/Phuket (p = 0.038) strain and higher pre- Notably, a greater proportion of subjects seroconverted to novel vaccine GMT for the H3N2/Hong Kong strain (p = 0.031). strains in a particular year, compared with the recurring strains Antibody responses were largely similar in women and men present in the vaccine formulation every year. For example, the (Supplementary Table 3). Pre-vaccination antibody titres to the recurring H1N1/California strain and both B vaccine strains of H1N1/California strain were significantly lower in women than in Brisbane and Phuket, elicited seroconversion in 27%, 32% and men, but this difference was not statistically significant after 31.9% of study participants respectively, whereas the novel strains vaccination. used in each vaccine season (H3N2/Hong Kong, H1N1/Michigan and H3N2/Switzerland), elicited seroconversion in a larger proportion of study participants: 54%, 36% and 48%, respectively. Regression analyses of antibody responses These differences in seroconversion were statistically significant Multiple logistic regression analyses indicated that vaccine year, for H3N2/Hong Kong and H3N2/Switzerland, but not H1N1/ vaccine strain, and study site were all independently associated Michigan. with the ability to seroconvert at day 28 p.i. (Supplementary Table Although the magnitude of post-vaccine antibody response 4a). Of note, disease status (COPD or healthy) was not varies considerably between strains, all strains elicited a sig- independently associated with seroconversion or post-vaccine nificantly higher post-vaccine geometric mean titre (GMT) than seroprotection. their corresponding pre-vaccine GMT (Fig. 2). Furthermore, the Although vaccine strain and year were identified as factors post-vaccine GMT for all strains increased above 1:40, independently associated with seroconversion and seroprotection Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 Proportion Seroconverted H1N1/California B/Phuket B/Brisbane H3N2/HongKong H1N1/Michigan H3N2/Switzerland Titre (Geometric Mean Titre ±95% CI) N. Snape et al. npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences Table 3. Vaccine response pre- (D0) and post- (D28) vaccine: Seroprotection rate, Seroconversion rates, and GMT for each vaccine strain. Vaccine strain Disease status N Pre- p value adjusted adj OR Post- p value adjusted OR adj OR Seroconverted p value adjusted adj OR Pre-GMT p value Post- p value Seroprotection OR p value Seroprotection (95% CI) p value (% of subjects OR p value GMT rate (% of (95% CI) rate (% of with 4-fold Ab (95% CI) subjects with subjects with increase) Ab titres ≥ 1:40) Ab titres ≥ 1:40) H1N1_A/ Healthy 72 45.8 Ref 76.4 Ref 27.8 Ref 22.9 53.9 CALIFORNIA/ COPD 75 36 0.58 0.69 0.29 70.7 0.55 0.9 0.76 26.7 0.97 1.15 0.72 20.7 0.56 54.8 0.87 07/2009-like (0.34, 1.38) (0.4, 1.99) (0.53, 2.56) B/PHUKET/ Healthy 72 63.9 Ref 90.3 Ref 25 Ref 47.1 104 3073/2013-like COPD 75 74.7 0.8 0.76 0.55 92 0.94 1.43 0.6 38.7 0.11 2.28 0.038* 44.3 0.41 125 0.33 (0.31, 1.86) (0.37, 5.55) (1.06, 5.09) B/BRISBANE/ Healthy 57 72 Ref 91.4 Ref 29.8 Ref 44.4 115 60/2008-like COPD 61 80.3 0.39 2.59 0.09 96.7 0.38 5.19 0.08 34.4 0.74 1.05 0.91 52.5 0.820 165 0.14 (0.88, 7.98) (0.91, 43.35) (0.43, 2.58) H3N2_A/ Healthy 15 6.7 Ref 66.7 Ref 53.3 Ref 9.12 66.5 SWITZERLAND/ COPD 14 28.6 0.29 10.11 0.1 64.3 0.8 1.38 0.72 42.8 0.85 0.512 0.45 19 0.51 80 0.79 9715293/ 2013- (0.84, (0.23, 9.09) (0.08, 2.82) like 308.50) H3N2_A/HONG Healthy 25 48 Ref 92 Ref 56 Ref 29.5 99.9 KONG/4801/ COPD 34 70.6 0.137 2.51 0.13 88.2 0.970 0.49 0.49 52.9 0.98 0.861 0.79 81.6 0.023* 347 0.011* 2014-like (0.76, 8.69) (0.05, 3.41) (0.27, 2.66) H1N1_A/ Healthy 31 51.6 Ref 77.4 Ref 41.9 Ref 28 87.5 MICHIGAN/45/ COPD 27 51.8 0.81 0.89 0.84 74.1 0.99 0.9 0.86 29.6 0.48 0.64 0.43 30.1 0.95 86.4 0.94 2015-like (0.30, 2.60) (0.26, 3.12) (0.20, 1.94) Differences between COPD compared with older healthy subjects calculated by: Wilcoxon ranked sum test (GMT); Chi-Square test with Yates’ correction (proportions); OR calculated from GLM adjusted for gender, age, year, and site. Ab antibody, GMT geometric mean titre, GLM generalised linear model, HI haemagglutination inhibition, OR odds ratio; Ref reference. * Significant difference (p value ≤ 0.05). N. Snape et al. (Supplementary Table 4a and b, respectively), analysis of the influenza vaccines in comparison to younger adults , our study interaction between vaccine strain and year demonstrated that demonstrated that older adults can be more responsive to the variation from one year to another could largely be attributed influenza strains to which they have not been exposed to in to vaccine strain, with some strains exhibiting collinearity with preceding years. Others have observed similar trends in adults, year (Supplementary Table 9). whereby participants had relatively high pre-vaccination HI titres Unadjusted univariate linear models suggest that the magni- but lower rises in post-vaccination HI titres after repeated tude of the fold increase in post-vaccine antibody levels was vaccination, compared with first-time vaccine recipients . Andrew negatively correlated with baseline antibody levels (p < 0.0001), et al. proposed that pre-existing antibodies mask de novo and positively correlated with body mass index (BMI; p < 0.0001), antibody responses, and Huang et al. further suggested that (Supplementary Table 5). Contrary to expectations, current pre-existing antigen-specific antibodies might mask viral epitopes smoking and total pack years were not associated with and thereby reduce the magnitude of secondary antibody 25,26 seroconversion, whereas cumulative passive smoke exposure response to repeated influenza exposure . Similarly, was positively associated with ability to seroconvert (Supplemen- Nuñezet al. reported that the impact of pre-existing immunity tary Table 6). on responses to influenza vaccination differed between older and We also assessed whether any self-reported comorbidities were younger subjects . It is, however, recognised that older adults are associated with seroconversion or seroprotection including more likely to have been previously exposed to influenza through asthma, bronchiectasis, hypertension, high cholesterol, heart contact with the virus or vaccination, which can provide a conditions and diabetes. generalised linear model (GLM) analysis protective effect to influenza via broadly cross-reactive existing 28–30 indicated that hypertension was the only comorbidity associated cellular immunity . with vaccine responses: those with hypertension showed a Greater than 90% of our study participants received the greater ability to seroconvert (p = 0.0491) than those without influenza vaccine in at least one of the two years prior to our hypertension (Supplementary Table 7a). However, hypertension study, and were thus an antigen-experienced population. was not associated with post-vaccine seroprotection (Supple- Participants at this life stage are likely to have previously been mentary Table 7b). exposed to a number of wild-type influenza viral infections, which Participants from Melbourne were more likely to seroconvert are known to induce more sustained protection to specific strains than participants from Brisbane (p = 0.0178; Supplementary Table than vaccination and may account for the high pre-vaccine HI 4a) and had a greater likelihood of attaining seroprotection after levels observed in our study. Evidence from large datasets vaccination (p = 0.0130) (Supplementary Table 4b). As noted suggests that repeated vaccination does not impact on the ability above, Brisbane and Melbourne study participants had similar of influenza vaccines to reduce hospitalisations due to influenza . demographic and clinical features (Supplementary Table 1). A meta-analysis of data from children and adults has also shown Baseline neutrophil, monocyte, and eosinophil numbers in no support for a reduction in VE of two consecutive influenza whole blood were significantly greater in COPD patients than in vaccines, however, there is some evidence from this study that healthy participants (Supplementary Fig. 1). However, GLM serial vaccination from greater than two consecutive seasons may analysis indicated that these leucocyte populations were not have negative impact on protection . Additionally, high pre- associated with seroconversion or seroprotection at D28 p.i. vaccine antibody levels have been shown to reduce the incidence (Supplementary Table 8a and b, respectively). of influenza infections in the elderly . The COPD cohort in our study included more males, was slightly older, and had more current and prior smoke exposure than the DISCUSSION healthy cohort. Despite the demographics not being completely We examined immune responses to the seasonal influenza matched between study groups, we observed no significant vaccine in COPD patients and healthy elderly people, most of difference in HI titre, for any strain, between healthy and COPD whom had previously been vaccinated. The major finding to groups. This is contrary to our previous pilot study, which found emerge was the extent to which vaccine strain was a key lower post-vaccine HI titres to H1N1 antigen in COPD patients independent predictor of seroconversion. The greatest degrees of compared to healthy participants . The disparity in VE between seroconversion were seen for novel vaccine strains, whereas lesser these two studies may be due the small size of the pilot study, or a responses were seen with recurring vaccine strains. Contrary to our mismatch in vaccine antigens in some years, which would reduce expectations, there was no evidence that COPD patients had sub- ability to mount a suitable immune response in those years .We optimal vaccine responses relative to healthy older participants. have also shown herein that disease status (COPD or healthy), We have shown that while many participants had high existing current smoking and comorbid disease (aside from hypertension), antibody titres, indicating they were already protected against were not associated with the efficacy of the influenza vaccine, certain strains, vaccinating with the same influenza strains in whether assessed by seroconversion or seroprotection. Other consecutive years failed to significantly augment the antibody studies report similar findings: VE in one older population was not response, whereas vaccinating with novel strains was more likely associated with comorbid disease , while another study reported to induce the desired outcome of seroconversion. For example, that VE in an elderly, vaccine-naïve population was not associated while study participants showed pre-vaccination GMT at or above with COPD severity, age, gender and current smoking status . the level of protection (HI titre ≥ 40) for both B/ antigens, relatively Given our study population was restricted to a relatively narrow, few individuals seroconverted to these strains. In contrast, the older range, it is perhaps not surprising that we observed no novel H3N2 strains stimulated greater seroconversion rates association between VE and age. relative to recurring strains. Similarly, a previous systematic review Interestingly, cumulative exposure to passive smoke was and meta-analysis has also shown that influenza vaccine effec- positively associated with ability to seroconvert which is 22 14 tiveness (VE) can differ greatly by subtype . Tsang et al. unexpected, considering that current smoking and cumulative conducted a systems biological approach in healthy adults, in pack years were not associated with any outcome measures in this order to develop models that predict responses to influenza study. Further studies in larger cohorts are needed. perturbation. They discovered that subjects with higher initial Melbourne study participants were more likely to seroconvert titres had lower fold changes at day 70 post-vaccine, also than Brisbane study participants, with no demographic or clinical suggesting this inverse correlation may be due to, along with differences between participants from these two large Australian other factors, inhibitory responses in pre-immune subjects . cities. One report suggested that influenza outbreaks are more Although older adults in general conventionally respond poorly to intense in regions with small population sizes and higher Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 N. Snape et al. humidity , while others have shown various environmental all residing in nursing homes and characteristically frail individuals factors including temperature, humidity and pollution influence with potential additional health impacts, concern regarding high 38,39 the incidence of influenza . Given the climatic differences rates of viral infection in individuals that still elicit reasonable between Brisbane (latitude 27.4° south: sub-tropical) and Mel- antibody levels may be extrapolated to immunocompromised bourne (latitude 37.8° south: temperate), it is possible that individuals such as those with COPD . Furthermore, the rate of differences in key environmental factors such as pollution, decline in antibody titres after vaccination remains troubling, sunlight exposure and vitamin D status may impact individual particularly in the elderly where clinical protection is not likely to immune response to vaccines . These observations are interest- persist year-round . Recent studies have demonstrated that ing and warrant further investigations in larger cohorts. antibody titres in the elderly are only elevated for 48-56 days after We acknowledge that our study has limitations. The choice of vaccination with the annual, trivalent, split-virus influenza vaccine, vaccine formulation in each year is regulated by the Australian consisting of two A strains and one B strain, and may not be government, making it difficult to compare specific vaccine strain further increased by a second booster of this same vaccine . responses across multiple years. Although we were able to In conclusion, while our findings provide reassurance that compare longitudinal data for some strains, this was not possible influenza vaccination is immunogenic in both COPD patients and for those strains occurring only in one vaccine season. Accord- healthy older people, there is clearly room for further improve- ingly, our study may be slightly underpowered for evaluating ment. Our findings raise the issue of whether the influenza vaccine these novel strains. We considered combining responses from should be personalised each year based on pre-existing antibody different years for H1 strains and H3 strains, as per McElhaney titres in order to target vaccine formulations to fill gaps in 41 42 et al. and Nunzi et al. , however, we did not use this approach individual antibody repertoires. Moving towards a more indivi- due to the clear variability in reactivity between strains. Circulating dualised seasonal approach, instead of the current blanket strains of influenza vary each year, making it difficult to interpret recommendation across the population, might increase the pre- and post-vaccine HI titres, particularly in regard to cross- efficacy of the influenza vaccine each year, and reduce the reactivity between strains. Furthermore, relying on vaccine- burden of influenza in vulnerable groups such as COPD patients. induced antibody response as a correlate of protection against This approach warrants formal testing in well-designed clinical influenza disregards important changes in cellular immunity and trials. enhanced vaccine-mediated protection against influenza in the 11,43 elderly . Data presented in this manuscript are not yet comprehensive enough to allow us to determine the mechanisms METHODS involved in such varied response to the chosen annual vaccine Study population, ethical and regulatory approvals strains, yet we speculate that potential mechanisms such as This non-randomised, unblinded, observational study was conducted in accelerated immunosenescence play a critical role . We continue accordance with the Declaration of Helsinki Principles and the Australian to look at the underlying mechanisms contributing to poor National Health and Medical Research Council (NHMRC) Code of Practice. influenza vaccine responsiveness, and are currently analysing Ethical approval was granted from local ethics committees: Metro South Health Human Research Committee (approval number: HREC/09/QPAH/ additional data from this study, including strain-specific B cell 297) and The University of Queensland Human Ethics Research Office induction. This is an area of current research in our laboratories. (approval number: 2011000502). All participants provided written informed Our study was not powered to evaluate the longer-term benefits consent prior to enrolment. of influenza vaccination on COPD exacerbations, though it is Eligible participants aged at or greater than 50 years were recruited from important that future studies address this issue. Despite these hospitals in two large Australians cities (Brisbane and Melbourne) between limitations, our study provides important insights into influenza 2015 and 2017. COPD patients had a current clinical diagnosis of mild-to- vaccine responses in healthy older and COPD populations over very-severe COPD, a post-bronchodilator forced expiratory volume in one time, and how these differ for each vaccine antigen. second (FEV of <80% predicted, and an FEV /FVC (forced vital capacity) 1) 1 In light of the recent COVID-19 pandemic, concern has been ratio <0.7, with no COPD exacerbations in the 28 days prior to enrolment, raised regarding the co-circulation of seasonal influenza and SARS- and stable medication use. Healthy participants were spouses or partners CoV-2, particularly in vulnerable populations. The overall risk to of COPD patients or were recruited through advertising. A standardised clinical questionnaire was used for screening and assessment. Inclusion health and mortality is higher with SARS-CoV-2 than influenza, and and exclusion criteria are further detailed in the Supplementary Methods. it appears that co-infection elicits no worse symptoms than having 45,46 Patients reporting additional physician-diagnosed pulmonary diseases SARS-CoV-2 alone . A study conducted by the national were eligible for inclusion provided COPD was the principal pulmonary Veterans Health Administration (USA) has, however, indicated diagnosis. The consort diagram shows the numbers recruited, screened the risks for exacerbations of asthma and COPD in this older and enroled in the study (Fig. 3). population to be higher in patients hospitalised with influenza compared with SARS-CoV-2 . As the simultaneous circulation of Study design SARS-CoV-2 and influenza strains continues to be a threat to Recruitment occurred between February and May each study year, prior to health, it becomes more important for greater uptake of the the southern-hemisphere winter. Clinical assessment questionnaire, blood annual influenza vaccine in these at-risk groups. The capacity to collection and spirometry were performed at the first clinic visit (day 0), reduce hospitalisations due to COPD exacerbations and other prior to intramuscular administration of a single standard dose of the influenza induced indications, alleviating services to better cope seasonal inactivated, trivalent or quadrivalent, split-virion influenza vaccine 47,48 with COVID-19 complications, is not insignificant . (FluQuadri™, Sanofi Pasteur). The vaccine consisted of 15 μg HA of each A central finding of this study is that previous exposure to a strain without adjuvant: Table 1 lists the vaccine composition in each year. specificinfluenza strain limits the subsequent magnitude of Study participants returned for further blood collection 28 days p.i. to response, or “boosting” ability, to that strain in ensuing seasonal determine serum antibody levels. Further information regarding study design can be found in the Supplementary Methods. vaccines. Based on seroprotection rates alone, the COPD patients and healthy older participants in our study may appear to be relatively well protected against influenza. However, the findings Immunogenicity of Camilloni et al. sound a note of caution in this regard: High rates Haemagglutination inhibition (HI) assays were performed against compo- of infection were seen in an immunised elderly population nents of each vaccine strain, following pre-treatment of sera with receptor- exposed to mismatched influenza B viruses, even though destroying enzyme, as per methods described by the World Health vaccination had significantly boosted HI titres of cross-reactive Organization , and outlined in the Supplementary Methods. Seroconver- antibodies . Although participants in Camilloni et al.’s study were sion was defined as fourfold increase in antibody HI titre above 1:40 post- npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences N. Snape et al. Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article. DATA AVAILABILITY The data generated as a result of this research project will be managed according to The University of Queensland’s Research Data Management Policy. This policy was developed to ensure that research data are properly managed according to recommendations made in The Australian Code for the Responsible Conduct of Research and applicable legislation. Managed dataset/s associated with this project metadata will also be available to view following a request to the authors (mediated access). This data will be retained for at least five years. Received: 7 June 2021; Accepted: 24 November 2021; REFERENCES 1. Brusselle,G.G., Joos,G. F.&Bracke,K.R. New insights into theimmunology of chronic obstructive pulmonary disease. Lancet 378, 1015–1026 (2011). 2. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease; 2020 report. https://goldcopd.org/gold-reports/ (2020). 3. Gershon, A. S. et al. Health services burden of undiagnosed and overdiagnosed COPD. Chest 153, 1336–1346 (2018). 4. Yang, I. A. et al. COPD-X Australian and New Zealand guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2017 update. Med. J. Aust. 207, 436–442 (2017). 5. Bekkat-Berkani, R. et al. Seasonal influenza vaccination in patients with COPD: a systematic literature review. BMC Pulm. Med. 17, 79 (2017). 6. Wedzicha, J. A. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 1, 115–120 (2004). 7. Schanzer, D. L., Saboui, M., Lee, L., Nwosu, A. & Bancej, C. Burden of influenza, respiratory syncytial virus, and other respiratory viruses and the completeness of respiratory viral identification among respiratory inpatients, Canada, 2003-2014. Influenza Other Respirator Viruses 12, 113–121 (2018). 8. Thompson, M. G. et al. Estimates of Deaths Associated with Seasonal Influenza— United States, 1976–2007. Morb. Mortal. Wkly. Rep. 59, 1057–1062 (2010). 9. Reber, A. J. et al. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis. 3,68–90 (2012). 10. Kim, J. H. et al. High-dose influenza vaccine favors acute plasmablast responses Fig. 3 Consort diagram for the study “Using influenza vaccination rather than long-term cellular responses. Vaccine 34, 4594–4601 (2016). to understand and improve immune responses to vaccination in 11. McElhaney, J. E. Influenza vaccine responses in older adults. Ageing Res. Rev. 10, patients with COPD and healthy older people (IVC)”. A flow 379–388 (2011). diagram of the progress through the phases of a non-randomised, 12. Haq, K. & McElhaney, J. E. Immunosenescence: influenza vaccination and the unblinded, observational study. elderly. Curr. Opin. Immunol. 29,38–42 (2014). 13. Nath, K. D. et al. Clinical factors associated with the humoral immune response to influenza vaccination, also known to be associated with a reduced risk of influenza vaccination in chronic obstructive pulmonary disease. Int. J. Chronic influenza infection . Seroprotection was defined as a HI titre ≥1:40, an Obstr. Pulm. Dis. 9,51–56 (2014). antibody level traditionally correlated with reduced risk of influenza 14. Gross, P. A., Quinnan, G. V., Weksler, M. E., Setia, U. & Douglas, R. G. Relation of 53,54 infection . Blood collection and sample processing are described in the chronic disease and immune response to influenza vaccine in the elderly. Vaccine Supplementary Methods. Baseline whole blood leucocyte counts were 7, 303–308 (1989). measured as standard of care. 15. Centres for Disease Control and Prevention. Influenza(Flu) Past Seasons Vaccine Effectivenes, https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates. html?web=1&wdLOR=cD4ED0E1F-CD53-4005-A613-BD4BF9FADF1A (2020). Statistical analysis 16. Gillard, P. et al. Long-term outcome of the humoral and cellular immune response of an H5N1 adjuvanted influenza vaccine in elderly persons: 2-year Descriptive statistics were calculated separately for each vaccine strain. follow-up of a randomised open-label study. Trials 15, 419 (2014). Vaccine responses were described as seroconversion and seroprotection 17. Chuaychoo, B. et al. Comparison of immunogenicity between intradermal and rates and as back-transformed GMT. Participants who did not supply blood intramuscular injections of repeated annual identical influenza virus strains post- samples at both baseline and 28 days p.i. were excluded from the analysis. pandemic (2011-2012) in COPD patients. Hum. Vaccin. Immunother. 16, A p value of <0.05 was considered to be statistically significant. Clinical 1371–1379 (2020). correlations, GLMs and regression models were generated using R (version 18. Ustinov, N. B., Zavyalova, E. G., Smirnova, I. G. & Kopylov, A. M. The power and 4.0.2, 2020, The R Foundation for Statistical Computing Platform, Vienna, limitations of influenza virus hemagglutinin assays. Biochemistry 82, Austria). Graphs were generated in R and GraphPad Prism, version 8.4.2 1234–1248 (2017). (464), (GraphPad Software, San Diego, CA, USA, www.graphpad.com). 19. Krammer, F. The human antibody response to influenza A virus infection and vaccination. Nat. Rev. Immunol. 19, 383–397 (2019). 20. Kopsaftis, Z., Wood-Baker, R. & Poole, P. Influenza vaccine for chronic obstructive Clinical study registration pulmonary disease (COPD). Cochrane Database Syst Rev. https://doi.org/10.1002/ This study is registered with Australian New Zealand Clinical Trials Registry 14651858.CD002733.pub3 (2018). (ANZCTR), under the title “Using influenza vaccination to understand and 21. Wongsurakiat, P. et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 125, improve immune responses to vaccination in patients with COPD and 2011–2020 (2004). healthy older people.” Registration number: ACTRN: ACTRN12620000830998. Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 N. Snape et al. 22. Belongia, E. A. et al. Variable influenza vaccine effectiveness by subtype: a sys- 50. Young, B. et al. Do antibody responses to the influenza vaccine persist year-round tematic review and meta-analysis of test-negative design studies. Lancet Infect. in the elderly? A systematic review and meta-analysis. Vaccine 35, 212–221 Dis. 16, 942–951 (2016). (2017). 23. Tsang, J. S. et al. Global analyses of human immune variation reveal baseline 51. Network, W. G. I. S. Manual for the Laboratory Diagnosis and Virological Surveil- predictors of postvaccination responses. Cell 157, 499–513 (2014). lance of Influenza (WHO Press, 2011). 24. Merani, S., Kuchel, G. A., Kleppinger, A. & McElhaney, J. E. Influenza vaccine-mediated 52. Beyer, W. E. P., Palache, A. M., Lüchters, G., Nauta, J. & Osterhaus, A. D. M. E. protection in older adults: Impact of influenza infection, cytomegalovirus serostatus Seroprotection rate, mean fold increase, seroconversion rate: which parameter and vaccine dosage. Exp Gerontol. https://doi.org/10.1016/j.exger.2017.09.015 (2017). adequately expresses seroresponse to influenza vaccination? Virus Res. 103, 25. Huang, K.-Y. A., Chang, S.-C., Huang, Y.-C., Chiu, C.-H. & Lin, T.-Y. Antibody 125–132 (2004). responses to trivalent inactivated influenza vaccine in health care personnel 53. Salk, J. E., Menke, W. J. Jr. & Francis, T. Jr. A clinical epidemiological and immu- previously vaccinated and vaccinated for the first time. Sci. Rep. 7, 40027 (2017). nological evaluation of vaccination against epidemic influenza. Am. J. Epidemiol. 26. Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell 42,57–93 (1945). responses to influenza. Sci. Transl. Med. 7, 316ra192 (2015). 54. Hannoun, C., Megas, F. & Piercy, J. Immunogenicity and protective efficacy of 27. Nuñez, I. A. et al. Impact of age and pre-existing influenza immune responses in influenza vaccination. Virus Res. 103, 133–138 (2004). humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza A strains. PLoS ONE 12, e0185666 (2017). 28. Nienen, M. et al. The role of pre-existing cross-reactive central memory CD4 ACKNOWLEDGEMENTS T-cells in vaccination with previously unseen influenza strains. Front. Immunol. 10, We would like to sincerely thank the participants of this study, the research nurses 593–593 (2019). and the hospitals involved in this study. We thank the funding body, National Health 29. Li, G. M. et al. Pandemic H1N1 influenza vaccine induces a recall response in & Medical Research Council (NHMRC), Australia (grant number #APP1081433), for humans that favors broadly cross-reactive memory B cells. Proc. Natl Acad. Sci. supporting this study. We also thank the reviewers for providing their time and USA 109, 9047–9052 (2012). comments to improve this manuscript. 30. Trieu, M. C. et al. Long-term maintenance of the influenza-specific cross-reactive memory CD4+ T-cell responses following repeated annual influenza vaccination. J. Infect. Dis. 215, 740–749 (2017). AUTHOR CONTRIBUTIONS 31. Hoa, L. N. M. et al. Influenza A(H1N1)pdm09 but not A(H3N2) virus infection G.P.A., J.W.U. and L.B.I. conceived and designed the experiments. N.S., A.G.J., A.C.H., induces durable sero-protection: results from the Ha Nam Cohort. J. Infect. Dis. Y.X. and T.C. performed acquisition of data and experimental analysis. N.S. and A.J. https://doi.org/10.1093/infdis/jiaa293 (2020). conducted data analysis and drafted the manuscript. N.S., A.J., A.C.H., G.P.A. and J.W. 32. Cheng, A. C. et al. Repeated vaccination does not appear to impact upon influ- U. contributed to the interpretation and critical revision of the data. A.J., J.W.U. and enza vaccine effectiveness against hospitalization with confirmed influenza. Clin. G.P.A. revised the manuscript. All authors read and approved the final manuscript. Infect. Dis. 64, 1564–1572 (2017). 33. Bartoszko, J. J. et al. Does consecutive influenza vaccination reduce protection against influenza: a systematic review and meta-analysis. Vaccine 36, 3434–3444 (2018). COMPETING INTERESTS 34. Govaert, T. E. et al. The efficacy of influenza vaccination in elderly individuals: a randomized double-blind placebo-controlled trial. JAMA 272, 1661–1665 (1994). Theauthors declarethe following financial interests/personal relationships which 35. Burel, J. G. et al. Evaluation of immune responses to influenza vaccination in may be considered as potential competing interests: J.W.U. declares: Support for chronic obstructive pulmonary disease. J. Vaccines Vaccin. S4, 001 (2012). the present manuscript from National Health & Medical Research Council 36. Kimball, J., Zhu, Y., Wyatt, D., Trabue, C. H. & Talbot, H. K. Influenza Vaccine Failure (Australia) for project grant funding to the University of Queensland. A.C.H. Associated with Age and Immunosuppression. J. Infect. Dis. https://doi.org/ declares: ACH currently works for Roche, a manufacturer of influenza antivirals. A. 10.1093/infdis/jiaa757 (2020). C.H. owns stock in Roche. A.C.H.’s involvement in the study was prior to being 37. Dalziel, B. D. et al. Urbanization and humidity shape the intensity of influenza employed by Roche. All other authors declare that they have no known conflict of epidemics in U.S. cities. Science 362, 75 (2018). interests. 38. Lowen, A. C. & Steel, J. Roles of humidity and temperature in shaping influenza seasonality. J. Virol. 88, 7692 (2014). 39. Tamerius, J. D. et al. Environmental predictors of seasonal influenza epidemics ADDITIONAL INFORMATION across temperate and tropical climates. PLoS Pathog. 9, e1003194 (2013). Supplementary information The online version contains supplementary material 40. Hart, P. H., Gorman, S. & Finlay-Jones, J. J. Modulation of the immune system by available at https://doi.org/10.1038/s41541-021-00422-4. UV radiation: more than just the effects of vitamin D? Nat. Rev. Immunol. 11, 584–596 (2011). Correspondence and requests for materials should be addressed to John W. Upham. 41. McElhaney, J. E. et al. Predictors of the antibody response to influenza vaccination in older adults with type 2 diabetes. BMJ Open Diabetes Res. Care 3, e000140 (2015). Reprints and permission information is available at http://www.nature.com/ 42. Nunzi, E., Iorio, A. M. & Camilloni, B. A 21-winter seasons retrospective study of reprints antibody response after influenza vaccination in elderly (60–85 years old) and very elderly (>85 years old) institutionalized subjects. Hum. Vaccin. Immunother. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 13, 2659–2668 (2017). in published maps and institutional affiliations. 43. Ohmit, S. E., Petrie, J. G., Cross, R. T., Johnson, E. & Monto, A. S. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J. Infect. Dis. 204, 1879–1885 (2011). 44. Crooke, S. N., Ovsyannikova, I. G., Poland, G. A. & Kennedy, R. B. Immunosenes- Open Access This article is licensed under a Creative Commons cence and human vaccine immune responses. Immun. Ageing 16, 25 (2019). Attribution 4.0 International License, which permits use, sharing, 45. Ludwig, M., Jacob, J., Basedow, F., Andersohn, F. & Walker, J. Clinical outcomes adaptation, distribution and reproduction in any medium or format, as long as you give and characteristics of patients hospitalized for Influenza or COVID-19 in Germany. appropriate credit to the original author(s) and the source, provide a link to the Creative Int J. Infect. Dis. 103, 316–322 (2021). Commons license, and indicate if changes were made. The images or other third party 46. Cates, J. et al. In Morbidity and Mortality Weekly Report Vol. 69 (ed US Department of material in this article are included in the article’s Creative Commons license, unless Health and Human Services) (Centres for Disease Control and Prevention, 2020). indicated otherwise in a credit line to the material. If material is not included in the 47. Grech, V. & Borg, M. Influenza vaccination in the COVID-19 era. Early Hum. Dev. article’s Creative Commons license and your intended use is not permitted by statutory 148, 105116 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 48. Capone, A. Simultaneous circulation of COVID-19 and flu in Italy: Potential from the copyright holder. To view a copy of this license, visit http://creativecommons. combined effects on the risk of death? Int. J. Infect. Dis. 99, 393–396 (2020). org/licenses/by/4.0/. 49. Camilloni, B. et al. An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home. Vaccine 28, 7536–7541 (2010). © The Author(s) 2022 npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Vaccines Springer Journals

Vaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy older people

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www.nature.com/npjvaccines ARTICLE OPEN Vaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy older people 1 2 3 2 4,6 5 1 Natale Snape , Gary P. Anderson , Louis B. Irving , Andrew G. Jarnicki , Aeron C. Hurt , Tina Collins , Yang Xi and 1,5 John W. Upham Though clinical guidelines recommend influenza vaccination for chronic obstructive pulmonary disease (COPD) patients and other high-risk populations, it is unclear whether current vaccination strategies induce optimal antibody responses. This study aimed to identify key variables associated with strain-specific antibody responses in COPD patients and healthy older people. 76 COPD and 72 healthy participants were recruited from two Australian centres and inoculated with influenza vaccine. Serum strain-specific antibody titres were measured pre- and post-inoculation. Seroconversion rate was the primary endpoint. Antibody responses varied between vaccine strains. The highest rates of seroconversion were seen with novel strains (36–55%), with lesser responses to strains included in the vaccine in more than one consecutive year (27–33%). Vaccine responses were similar in COPD patients and healthy participants. Vaccine strain, hypertension and latitude were independent predictors of seroconversion. Our findings reassure that influenza vaccination is equally immunogenic in COPD patients and healthy older people; however, there is room for improvement. There may be a need to personalise the yearly influenza vaccine, including consideration of pre-existing antibody titres, in order to target gaps in individual antibody repertoires and improve protection. npj Vaccines (2022) 7:8 ; https://doi.org/10.1038/s41541-021-00422-4 INTRODUCTION this study showed that influenza vaccination reduced COPD exacerbations relative to placebo, it is notable that the active Chronic obstructive pulmonary disease (COPD) is a common, serious intervention group received double the recommended vaccine lung disease caused by smoking and exposure to air pollutants . dose . In contrast, we previously reported that the humoral COPD is the third leading cause of mortality worldwide with the immune response to influenza vaccination may be sub-optimal in global disease burden likely to increase substantially in coming 3,4 COPD . There is considerable lack of knowledge regarding the years . Common respiratory viruses such as rhinoviruses and 5,6 immune response to influenza vaccine in COPD patients— influenza often trigger COPD exacerbations ,and can lead to whether the current vaccine strategy is sufficiently immunogenic secondary bacterial infections, hospitalisations and death . Clinical and whether subgroups of patients fail to mount a robust guidelines recommend influenza vaccination as a priority for COPD antibody response. Addressing these knowledge gaps is necessary patients and other high-risk populations including the elderly and for developing better vaccine strategies for COPD patients and immune compromised . However, vaccine efficacy may be sub- other at-risk populations. optimal in these high-risk populations, either because of age-related 9–12 The aim of this study was to examine vaccine immunogenicity immune dysfunction known as immunosenescence ,orbecause 13,14 in COPD patients and age-matched healthy older people, in order of disease-specificdeficits in anti-viral immunity . to identify key variables associated with strain-specific antibody Vaccines act by inducing antibody production and long-lived responses. The primary study endpoint was seroconversion, memory B cells, however, influenza vaccine efficacy can be less 15 defined as ≥four-fold increase in haemagglutination inhibition than ideal . Post-vaccination, influenza antibody titres decline 16,17 (HI) antibody titre at 28 days post-inoculation (p.i.). Seroprotection, relatively quickly, particularly in the elderly , so annual (defined by the World Health Organisation (WHO) as an HI vaccination is required. Additionally, the influenza virus haemag- antibody titre ≥1:40) was a secondary endpoint. Notably, this glutinin (HA) and neuramidase surface proteins exhibit a high 18 study was not designed to assess whether vaccination reduces the propensity for antigenic drift and evasion of host antibodies ,so incidence of influenza infections or COPD exacerbations. vaccine formulations require updating annually. Strain selection for the vaccine each year is usually based on knowledge of strains circulating in the opposite hemisphere’s winter . RESULTS Recent systematic reviews have concluded that influenza vaccination is probably beneficial in COPD, though evidence gaps Influenza vaccine formulations were based on Australian Govern- remain , with relatively few randomised controlled trials (RCTs) ment recommendations and differed slightly across the study years directly assessing whether influenza vaccination reduces COPD 2015-2017 (Table 1). The H1N1_A/CALIFORNIA/07/2009-like and exacerbations . The largest RCT in the last 50 years was B_PHUKET/3073/2013-like strains were components in the approved conducted in predominantly vaccine naïve participants. Though vaccine formulation in all three years of this study, enabling greater 1 2 Faculty of Medicine, The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD, Australia. Lung Health Research Centre, Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, Australia. Department of Respiratory Medicine, The Royal Melbourne Hospital, Parkville, VIC, Australia. WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute 5 6 for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia. Metro South Health, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. Present address: Department of Infectious Diseases, Roche Pharma Research & Early Development, Basel, Switzerland. email: john_upham@health.qld.gov.au Published in partnership with the Sealy Institute for Vaccine Sciences 1234567890():,; N. Snape et al. Table 1. WHO-recommended southern-hemisphere influenza vaccine formulations for trivalent and quadrivalent vaccines for each vaccine year. 2015 2016 2017 H1N1_A/CALIFORNIA/07/2009-like H1N1_A/CALIFORNIA/07/2009-like H1N1_A/CALIFORNIA/07/2009-like B/PHUKET/3073/2013-like B/PHUKET/3073/2013-like B/PHUKET/3073/2013-like B/BRISBANE/60/2008-like B/BRISBANE/60/2008-like H3N2_A/SWITZERLAND/ 9715293/2013-like H3N2_A/HONG KONG/4801/2014-like H1N1_A/MICHIGAN/45/2015-like Table 2. Demographics and clinical characteristics of the study population: Comparative between COPD and older healthy participants. Demographic and Clinical Characteristics Total COPD Healthy p value (COPD vs healthy) N 147 75 72 ns Female—n (%) 60 (40.8) 23 (30.6) 37 (51.4) 0.01 Male—n (%) 87 (59.2) 52 (69.3) 35 (48.6) 0.01 Brisbane cohort 94 48 46 ns Melbourne cohort 53 27 26 ns 2016 returns from 2015 (%) 9 (6) 4 (5.3) 5 (6.9) 2017 returns from 2016 (%) 9 (6) 5 (6.6) 4 (5.5) Age (95% CI) Mean 66.8 (65.3–68.3) 68.7 (66.7–70.7) 64.9 (62.7–67.1) <0.01 Median 67 (64–69) 69 (67–71) 63 (60–68) Range 50–90 51–90 50–88 BMI (95% CI) Mean 28.1 (27.0–29.2) 28.3 (26.6–30.0) 27.9 (26.6–29.1) ns Median 26.7 (26.1–27.7) 26.6 (24.9–28.0) 26.9 (26.1–28.3) Range 18.2–52.9 18.2–52.9 19.0–44.4 Smoking status n (%) Never 40 (27.2) 5 (6.6) 35 (48.6) <0.0001 Former 84 (57.1) 49 (65.3) 35 (48.6) ns Current 23 (15.6) 21 (28) 2 (2.8) <0.0001 Pack Years (95% CI) Mean 31.3 (25.6–37.1) 51.6 (43.5–59.7) 10.2 (5.6–14.7) <0.0001 Median 21.0 (14.0–30.0) 44.5 (39.0–53.0) 0 (0–3) Range 0–168 0–168 0–76 Diabetes—n (%) 20 (13.6) 12 (16) 8 (11.1) ns Heart condition—n (%) 35 (23.8) 23 (30.6) 12 (16.7) ns Asthma—n (%) 23 (15.6) 18 (24) 5 (6.9) <0.01 Bronchiectasis—n (%) 6 (4.1) 6 (8) 0 <0.05 High blood pressue—n (%) 57 (38.8) 33 (44) 24 (33.3) ns High cholesterol—n (%) 52 (35.4) 27 (36) 25 (34.7) ns Mean FEV predicted % (95% CI) 74.0 (68.6–79.5) 48.7 (43.3–52.0) 102.7 (98.4–107) <0.0001 Mean FEV /FVC % (95% CI) 62.6 (59.1–66) 50.1 (45.4–54.9) 76.0 (73.8–78.3) <0.0001 Vaccine history n (%) Never 5 (3.4) 3 (4) 2 (2.8) ns Previous 2 years (both) 120 (81.6) 63 (84) 57 (79.2) ns Previous year (only) 11 (7.5) 7 (9.3) 4 (5.5) ns Year before previous (only) 4 (2.7) 1 (1.3) 3 (4.2) ns Ever before (except previous 2 years) 7 (4.8) 1 (1.3) 6 (8.3) ns Significance (p values) calculated by Welch’s t test (means) and Yates’ Chi-square test (proportions). ns not significant. statistical power in assessing responses to these strains. A Participant characteristics quadrivalent vaccine formulation in 2016 and 2017 added a second Participant demographics are shown in Table 2. The mean age of B strain (Brisbane/60/2008-like) to the previous trivalent vaccine. COPD participants was 3.8 years higher than that of healthy One strain differed each year, usually an H3N2 or H1N1 strain. participants (p < 0.01), and just under 70% of COPD participants npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences 1234567890():,; N. Snape et al. H1N1_California 0.80 B_Phuket ** B_Brisbane 0.70 4096 # H3N2_HongKong 0.60 H3N2_Switzerland H1H1_Michigan 0.50 0.40 0.30 0.20 0.10 0.00 0 28 0 28 0 28 0 28 0 28 0 28 Days post vaccine Fig. 2 Antibody response pre- (D0) and post- (D28) vaccine for each strain. Data is expressed as GMT ± 95% confidence intervals. Temporal differences for each strain are considered significant if confidence intervals (CI) do not overlap. Dotted horizontal line represents a GMT of 1:40, indicative of seroprotection. GMT: geometric mean titre. Fig. 1 Proportion of subjects that seroconverted (≥ 4-fold rise in Ab titre from D0). Data displayed as proportion ± standard error of demonstrating seroprotection. The high pre-vaccine GMT, seen fit. Red bars: recurring strains (present in vaccine ≥2 seasons), blue in both B strains and the novel strain H3N2/Hong Kong, indicates bars: novel strains in vaccine season. **significant difference (p < that our cohort already exhibited strain-specific seroprotection 0.001) to all recurring strains (H1N1/California, B/Phuket & B/ prior to vaccination. Interestingly, the two novel H3N2 vaccine Brisbane), significant difference (p < 0.05) to recurring strain H1N1/California only. Significance between proportions calculated strains (H3N2/Hong Kong & H3N2/Switzerland) induced greater by Yates’ Chi-square test. degrees of post-vaccine seroprotection, with H3N2/Hong Kong also eliciting a higher GMT, than the recurring strains (Fig. 2), were male, whereas the healthy participants comprised similar signifying that these two novel vaccine strains were particularly numbers of females and males. Compared with healthy partici- efficacious. pants, COPD patients had significantly greater cumulative smoke exposure (pack years), were more likely to be current smokers, and Comparative seroconversion and seroprotection rates more likely to report physician-diagnosed comorbidities, such as Antibody responses to the various vaccine strains were broadly asthma and bronchiectasis. Over 90% of our study population similar in the COPD and healthy participants. Few differences are received an influenza vaccine in at least one of the two years prior observed between COPD and healthy participants in either pre- or to enrolment. Population demographics were analogous across post-vaccine seroprotection, or in GMT (Table 3). Vaccine strain B/ the Brisbane and Melbourne study sites (Supplementary Table 1). Phuket elicited a significantly higher seroconversion rate in COPD Nine subjects participated in the study in consecutive years patients than in healthy participants (adjusted OR p = 0.038), and (2015 and 2016), and another nine participated in both 2016 and COPD patients had higher pre- and post-vaccine GMT to vaccine 2017. No subjects participated in three consecutive years. Because strain A/Hong Kong than healthy participants. These differences the influenza vaccine formulation varies by year and because were not seen with the other strains. clinical characteristics may fluctuate over time, these ‘repeat We further assessed whether strain-specific antibody responses participants’ were analysed as individual subjects within each varied by study location (Supplementary Table 2). Melbourne participating year. participants tended to have higher post-vaccine seroprotection rates and GMT than Brisbane participants, though differences Vaccine-induced antibody response vary by strain were only significant for the H1N1/California strain (p = 0.03, adjOR p = 0.029 and GMT p ≤ 0.001). The H1N1/California strain We compared day 28 p.i. seroconversion rates for those strains also elicited a significantly higher seroconversion rate (p = 0.19, included in the vaccine formulation in more than one consecutive adjOR p = 0.012) in Melbourne relative to Brisbane participants. year (hereafter referred to as ‘recurring strains’), contrasting this Melbourne participants also had higher pre-vaccine seroprotec- with vaccine strains that were ‘novel’ to a vaccine season (Fig. 1). tion rates for the P/Phuket (p = 0.038) strain and higher pre- Notably, a greater proportion of subjects seroconverted to novel vaccine GMT for the H3N2/Hong Kong strain (p = 0.031). strains in a particular year, compared with the recurring strains Antibody responses were largely similar in women and men present in the vaccine formulation every year. For example, the (Supplementary Table 3). Pre-vaccination antibody titres to the recurring H1N1/California strain and both B vaccine strains of H1N1/California strain were significantly lower in women than in Brisbane and Phuket, elicited seroconversion in 27%, 32% and men, but this difference was not statistically significant after 31.9% of study participants respectively, whereas the novel strains vaccination. used in each vaccine season (H3N2/Hong Kong, H1N1/Michigan and H3N2/Switzerland), elicited seroconversion in a larger proportion of study participants: 54%, 36% and 48%, respectively. Regression analyses of antibody responses These differences in seroconversion were statistically significant Multiple logistic regression analyses indicated that vaccine year, for H3N2/Hong Kong and H3N2/Switzerland, but not H1N1/ vaccine strain, and study site were all independently associated Michigan. with the ability to seroconvert at day 28 p.i. (Supplementary Table Although the magnitude of post-vaccine antibody response 4a). Of note, disease status (COPD or healthy) was not varies considerably between strains, all strains elicited a sig- independently associated with seroconversion or post-vaccine nificantly higher post-vaccine geometric mean titre (GMT) than seroprotection. their corresponding pre-vaccine GMT (Fig. 2). Furthermore, the Although vaccine strain and year were identified as factors post-vaccine GMT for all strains increased above 1:40, independently associated with seroconversion and seroprotection Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 Proportion Seroconverted H1N1/California B/Phuket B/Brisbane H3N2/HongKong H1N1/Michigan H3N2/Switzerland Titre (Geometric Mean Titre ±95% CI) N. Snape et al. npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences Table 3. Vaccine response pre- (D0) and post- (D28) vaccine: Seroprotection rate, Seroconversion rates, and GMT for each vaccine strain. Vaccine strain Disease status N Pre- p value adjusted adj OR Post- p value adjusted OR adj OR Seroconverted p value adjusted adj OR Pre-GMT p value Post- p value Seroprotection OR p value Seroprotection (95% CI) p value (% of subjects OR p value GMT rate (% of (95% CI) rate (% of with 4-fold Ab (95% CI) subjects with subjects with increase) Ab titres ≥ 1:40) Ab titres ≥ 1:40) H1N1_A/ Healthy 72 45.8 Ref 76.4 Ref 27.8 Ref 22.9 53.9 CALIFORNIA/ COPD 75 36 0.58 0.69 0.29 70.7 0.55 0.9 0.76 26.7 0.97 1.15 0.72 20.7 0.56 54.8 0.87 07/2009-like (0.34, 1.38) (0.4, 1.99) (0.53, 2.56) B/PHUKET/ Healthy 72 63.9 Ref 90.3 Ref 25 Ref 47.1 104 3073/2013-like COPD 75 74.7 0.8 0.76 0.55 92 0.94 1.43 0.6 38.7 0.11 2.28 0.038* 44.3 0.41 125 0.33 (0.31, 1.86) (0.37, 5.55) (1.06, 5.09) B/BRISBANE/ Healthy 57 72 Ref 91.4 Ref 29.8 Ref 44.4 115 60/2008-like COPD 61 80.3 0.39 2.59 0.09 96.7 0.38 5.19 0.08 34.4 0.74 1.05 0.91 52.5 0.820 165 0.14 (0.88, 7.98) (0.91, 43.35) (0.43, 2.58) H3N2_A/ Healthy 15 6.7 Ref 66.7 Ref 53.3 Ref 9.12 66.5 SWITZERLAND/ COPD 14 28.6 0.29 10.11 0.1 64.3 0.8 1.38 0.72 42.8 0.85 0.512 0.45 19 0.51 80 0.79 9715293/ 2013- (0.84, (0.23, 9.09) (0.08, 2.82) like 308.50) H3N2_A/HONG Healthy 25 48 Ref 92 Ref 56 Ref 29.5 99.9 KONG/4801/ COPD 34 70.6 0.137 2.51 0.13 88.2 0.970 0.49 0.49 52.9 0.98 0.861 0.79 81.6 0.023* 347 0.011* 2014-like (0.76, 8.69) (0.05, 3.41) (0.27, 2.66) H1N1_A/ Healthy 31 51.6 Ref 77.4 Ref 41.9 Ref 28 87.5 MICHIGAN/45/ COPD 27 51.8 0.81 0.89 0.84 74.1 0.99 0.9 0.86 29.6 0.48 0.64 0.43 30.1 0.95 86.4 0.94 2015-like (0.30, 2.60) (0.26, 3.12) (0.20, 1.94) Differences between COPD compared with older healthy subjects calculated by: Wilcoxon ranked sum test (GMT); Chi-Square test with Yates’ correction (proportions); OR calculated from GLM adjusted for gender, age, year, and site. Ab antibody, GMT geometric mean titre, GLM generalised linear model, HI haemagglutination inhibition, OR odds ratio; Ref reference. * Significant difference (p value ≤ 0.05). N. Snape et al. (Supplementary Table 4a and b, respectively), analysis of the influenza vaccines in comparison to younger adults , our study interaction between vaccine strain and year demonstrated that demonstrated that older adults can be more responsive to the variation from one year to another could largely be attributed influenza strains to which they have not been exposed to in to vaccine strain, with some strains exhibiting collinearity with preceding years. Others have observed similar trends in adults, year (Supplementary Table 9). whereby participants had relatively high pre-vaccination HI titres Unadjusted univariate linear models suggest that the magni- but lower rises in post-vaccination HI titres after repeated tude of the fold increase in post-vaccine antibody levels was vaccination, compared with first-time vaccine recipients . Andrew negatively correlated with baseline antibody levels (p < 0.0001), et al. proposed that pre-existing antibodies mask de novo and positively correlated with body mass index (BMI; p < 0.0001), antibody responses, and Huang et al. further suggested that (Supplementary Table 5). Contrary to expectations, current pre-existing antigen-specific antibodies might mask viral epitopes smoking and total pack years were not associated with and thereby reduce the magnitude of secondary antibody 25,26 seroconversion, whereas cumulative passive smoke exposure response to repeated influenza exposure . Similarly, was positively associated with ability to seroconvert (Supplemen- Nuñezet al. reported that the impact of pre-existing immunity tary Table 6). on responses to influenza vaccination differed between older and We also assessed whether any self-reported comorbidities were younger subjects . It is, however, recognised that older adults are associated with seroconversion or seroprotection including more likely to have been previously exposed to influenza through asthma, bronchiectasis, hypertension, high cholesterol, heart contact with the virus or vaccination, which can provide a conditions and diabetes. generalised linear model (GLM) analysis protective effect to influenza via broadly cross-reactive existing 28–30 indicated that hypertension was the only comorbidity associated cellular immunity . with vaccine responses: those with hypertension showed a Greater than 90% of our study participants received the greater ability to seroconvert (p = 0.0491) than those without influenza vaccine in at least one of the two years prior to our hypertension (Supplementary Table 7a). However, hypertension study, and were thus an antigen-experienced population. was not associated with post-vaccine seroprotection (Supple- Participants at this life stage are likely to have previously been mentary Table 7b). exposed to a number of wild-type influenza viral infections, which Participants from Melbourne were more likely to seroconvert are known to induce more sustained protection to specific strains than participants from Brisbane (p = 0.0178; Supplementary Table than vaccination and may account for the high pre-vaccine HI 4a) and had a greater likelihood of attaining seroprotection after levels observed in our study. Evidence from large datasets vaccination (p = 0.0130) (Supplementary Table 4b). As noted suggests that repeated vaccination does not impact on the ability above, Brisbane and Melbourne study participants had similar of influenza vaccines to reduce hospitalisations due to influenza . demographic and clinical features (Supplementary Table 1). A meta-analysis of data from children and adults has also shown Baseline neutrophil, monocyte, and eosinophil numbers in no support for a reduction in VE of two consecutive influenza whole blood were significantly greater in COPD patients than in vaccines, however, there is some evidence from this study that healthy participants (Supplementary Fig. 1). However, GLM serial vaccination from greater than two consecutive seasons may analysis indicated that these leucocyte populations were not have negative impact on protection . Additionally, high pre- associated with seroconversion or seroprotection at D28 p.i. vaccine antibody levels have been shown to reduce the incidence (Supplementary Table 8a and b, respectively). of influenza infections in the elderly . The COPD cohort in our study included more males, was slightly older, and had more current and prior smoke exposure than the DISCUSSION healthy cohort. Despite the demographics not being completely We examined immune responses to the seasonal influenza matched between study groups, we observed no significant vaccine in COPD patients and healthy elderly people, most of difference in HI titre, for any strain, between healthy and COPD whom had previously been vaccinated. The major finding to groups. This is contrary to our previous pilot study, which found emerge was the extent to which vaccine strain was a key lower post-vaccine HI titres to H1N1 antigen in COPD patients independent predictor of seroconversion. The greatest degrees of compared to healthy participants . The disparity in VE between seroconversion were seen for novel vaccine strains, whereas lesser these two studies may be due the small size of the pilot study, or a responses were seen with recurring vaccine strains. Contrary to our mismatch in vaccine antigens in some years, which would reduce expectations, there was no evidence that COPD patients had sub- ability to mount a suitable immune response in those years .We optimal vaccine responses relative to healthy older participants. have also shown herein that disease status (COPD or healthy), We have shown that while many participants had high existing current smoking and comorbid disease (aside from hypertension), antibody titres, indicating they were already protected against were not associated with the efficacy of the influenza vaccine, certain strains, vaccinating with the same influenza strains in whether assessed by seroconversion or seroprotection. Other consecutive years failed to significantly augment the antibody studies report similar findings: VE in one older population was not response, whereas vaccinating with novel strains was more likely associated with comorbid disease , while another study reported to induce the desired outcome of seroconversion. For example, that VE in an elderly, vaccine-naïve population was not associated while study participants showed pre-vaccination GMT at or above with COPD severity, age, gender and current smoking status . the level of protection (HI titre ≥ 40) for both B/ antigens, relatively Given our study population was restricted to a relatively narrow, few individuals seroconverted to these strains. In contrast, the older range, it is perhaps not surprising that we observed no novel H3N2 strains stimulated greater seroconversion rates association between VE and age. relative to recurring strains. Similarly, a previous systematic review Interestingly, cumulative exposure to passive smoke was and meta-analysis has also shown that influenza vaccine effec- positively associated with ability to seroconvert which is 22 14 tiveness (VE) can differ greatly by subtype . Tsang et al. unexpected, considering that current smoking and cumulative conducted a systems biological approach in healthy adults, in pack years were not associated with any outcome measures in this order to develop models that predict responses to influenza study. Further studies in larger cohorts are needed. perturbation. They discovered that subjects with higher initial Melbourne study participants were more likely to seroconvert titres had lower fold changes at day 70 post-vaccine, also than Brisbane study participants, with no demographic or clinical suggesting this inverse correlation may be due to, along with differences between participants from these two large Australian other factors, inhibitory responses in pre-immune subjects . cities. One report suggested that influenza outbreaks are more Although older adults in general conventionally respond poorly to intense in regions with small population sizes and higher Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 N. Snape et al. humidity , while others have shown various environmental all residing in nursing homes and characteristically frail individuals factors including temperature, humidity and pollution influence with potential additional health impacts, concern regarding high 38,39 the incidence of influenza . Given the climatic differences rates of viral infection in individuals that still elicit reasonable between Brisbane (latitude 27.4° south: sub-tropical) and Mel- antibody levels may be extrapolated to immunocompromised bourne (latitude 37.8° south: temperate), it is possible that individuals such as those with COPD . Furthermore, the rate of differences in key environmental factors such as pollution, decline in antibody titres after vaccination remains troubling, sunlight exposure and vitamin D status may impact individual particularly in the elderly where clinical protection is not likely to immune response to vaccines . These observations are interest- persist year-round . Recent studies have demonstrated that ing and warrant further investigations in larger cohorts. antibody titres in the elderly are only elevated for 48-56 days after We acknowledge that our study has limitations. The choice of vaccination with the annual, trivalent, split-virus influenza vaccine, vaccine formulation in each year is regulated by the Australian consisting of two A strains and one B strain, and may not be government, making it difficult to compare specific vaccine strain further increased by a second booster of this same vaccine . responses across multiple years. Although we were able to In conclusion, while our findings provide reassurance that compare longitudinal data for some strains, this was not possible influenza vaccination is immunogenic in both COPD patients and for those strains occurring only in one vaccine season. Accord- healthy older people, there is clearly room for further improve- ingly, our study may be slightly underpowered for evaluating ment. Our findings raise the issue of whether the influenza vaccine these novel strains. We considered combining responses from should be personalised each year based on pre-existing antibody different years for H1 strains and H3 strains, as per McElhaney titres in order to target vaccine formulations to fill gaps in 41 42 et al. and Nunzi et al. , however, we did not use this approach individual antibody repertoires. Moving towards a more indivi- due to the clear variability in reactivity between strains. Circulating dualised seasonal approach, instead of the current blanket strains of influenza vary each year, making it difficult to interpret recommendation across the population, might increase the pre- and post-vaccine HI titres, particularly in regard to cross- efficacy of the influenza vaccine each year, and reduce the reactivity between strains. Furthermore, relying on vaccine- burden of influenza in vulnerable groups such as COPD patients. induced antibody response as a correlate of protection against This approach warrants formal testing in well-designed clinical influenza disregards important changes in cellular immunity and trials. enhanced vaccine-mediated protection against influenza in the 11,43 elderly . Data presented in this manuscript are not yet comprehensive enough to allow us to determine the mechanisms METHODS involved in such varied response to the chosen annual vaccine Study population, ethical and regulatory approvals strains, yet we speculate that potential mechanisms such as This non-randomised, unblinded, observational study was conducted in accelerated immunosenescence play a critical role . We continue accordance with the Declaration of Helsinki Principles and the Australian to look at the underlying mechanisms contributing to poor National Health and Medical Research Council (NHMRC) Code of Practice. influenza vaccine responsiveness, and are currently analysing Ethical approval was granted from local ethics committees: Metro South Health Human Research Committee (approval number: HREC/09/QPAH/ additional data from this study, including strain-specific B cell 297) and The University of Queensland Human Ethics Research Office induction. This is an area of current research in our laboratories. (approval number: 2011000502). All participants provided written informed Our study was not powered to evaluate the longer-term benefits consent prior to enrolment. of influenza vaccination on COPD exacerbations, though it is Eligible participants aged at or greater than 50 years were recruited from important that future studies address this issue. Despite these hospitals in two large Australians cities (Brisbane and Melbourne) between limitations, our study provides important insights into influenza 2015 and 2017. COPD patients had a current clinical diagnosis of mild-to- vaccine responses in healthy older and COPD populations over very-severe COPD, a post-bronchodilator forced expiratory volume in one time, and how these differ for each vaccine antigen. second (FEV of <80% predicted, and an FEV /FVC (forced vital capacity) 1) 1 In light of the recent COVID-19 pandemic, concern has been ratio <0.7, with no COPD exacerbations in the 28 days prior to enrolment, raised regarding the co-circulation of seasonal influenza and SARS- and stable medication use. Healthy participants were spouses or partners CoV-2, particularly in vulnerable populations. The overall risk to of COPD patients or were recruited through advertising. A standardised clinical questionnaire was used for screening and assessment. Inclusion health and mortality is higher with SARS-CoV-2 than influenza, and and exclusion criteria are further detailed in the Supplementary Methods. it appears that co-infection elicits no worse symptoms than having 45,46 Patients reporting additional physician-diagnosed pulmonary diseases SARS-CoV-2 alone . A study conducted by the national were eligible for inclusion provided COPD was the principal pulmonary Veterans Health Administration (USA) has, however, indicated diagnosis. The consort diagram shows the numbers recruited, screened the risks for exacerbations of asthma and COPD in this older and enroled in the study (Fig. 3). population to be higher in patients hospitalised with influenza compared with SARS-CoV-2 . As the simultaneous circulation of Study design SARS-CoV-2 and influenza strains continues to be a threat to Recruitment occurred between February and May each study year, prior to health, it becomes more important for greater uptake of the the southern-hemisphere winter. Clinical assessment questionnaire, blood annual influenza vaccine in these at-risk groups. The capacity to collection and spirometry were performed at the first clinic visit (day 0), reduce hospitalisations due to COPD exacerbations and other prior to intramuscular administration of a single standard dose of the influenza induced indications, alleviating services to better cope seasonal inactivated, trivalent or quadrivalent, split-virion influenza vaccine 47,48 with COVID-19 complications, is not insignificant . (FluQuadri™, Sanofi Pasteur). The vaccine consisted of 15 μg HA of each A central finding of this study is that previous exposure to a strain without adjuvant: Table 1 lists the vaccine composition in each year. specificinfluenza strain limits the subsequent magnitude of Study participants returned for further blood collection 28 days p.i. to response, or “boosting” ability, to that strain in ensuing seasonal determine serum antibody levels. Further information regarding study design can be found in the Supplementary Methods. vaccines. Based on seroprotection rates alone, the COPD patients and healthy older participants in our study may appear to be relatively well protected against influenza. However, the findings Immunogenicity of Camilloni et al. sound a note of caution in this regard: High rates Haemagglutination inhibition (HI) assays were performed against compo- of infection were seen in an immunised elderly population nents of each vaccine strain, following pre-treatment of sera with receptor- exposed to mismatched influenza B viruses, even though destroying enzyme, as per methods described by the World Health vaccination had significantly boosted HI titres of cross-reactive Organization , and outlined in the Supplementary Methods. Seroconver- antibodies . Although participants in Camilloni et al.’s study were sion was defined as fourfold increase in antibody HI titre above 1:40 post- npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences N. Snape et al. Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article. DATA AVAILABILITY The data generated as a result of this research project will be managed according to The University of Queensland’s Research Data Management Policy. This policy was developed to ensure that research data are properly managed according to recommendations made in The Australian Code for the Responsible Conduct of Research and applicable legislation. Managed dataset/s associated with this project metadata will also be available to view following a request to the authors (mediated access). This data will be retained for at least five years. Received: 7 June 2021; Accepted: 24 November 2021; REFERENCES 1. Brusselle,G.G., Joos,G. F.&Bracke,K.R. New insights into theimmunology of chronic obstructive pulmonary disease. Lancet 378, 1015–1026 (2011). 2. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease; 2020 report. https://goldcopd.org/gold-reports/ (2020). 3. Gershon, A. S. et al. Health services burden of undiagnosed and overdiagnosed COPD. Chest 153, 1336–1346 (2018). 4. Yang, I. A. et al. COPD-X Australian and New Zealand guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2017 update. Med. J. Aust. 207, 436–442 (2017). 5. Bekkat-Berkani, R. et al. Seasonal influenza vaccination in patients with COPD: a systematic literature review. BMC Pulm. Med. 17, 79 (2017). 6. Wedzicha, J. A. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 1, 115–120 (2004). 7. Schanzer, D. L., Saboui, M., Lee, L., Nwosu, A. & Bancej, C. Burden of influenza, respiratory syncytial virus, and other respiratory viruses and the completeness of respiratory viral identification among respiratory inpatients, Canada, 2003-2014. Influenza Other Respirator Viruses 12, 113–121 (2018). 8. Thompson, M. G. et al. Estimates of Deaths Associated with Seasonal Influenza— United States, 1976–2007. Morb. Mortal. Wkly. Rep. 59, 1057–1062 (2010). 9. Reber, A. J. et al. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis. 3,68–90 (2012). 10. Kim, J. H. et al. High-dose influenza vaccine favors acute plasmablast responses Fig. 3 Consort diagram for the study “Using influenza vaccination rather than long-term cellular responses. Vaccine 34, 4594–4601 (2016). to understand and improve immune responses to vaccination in 11. McElhaney, J. E. Influenza vaccine responses in older adults. Ageing Res. Rev. 10, patients with COPD and healthy older people (IVC)”. A flow 379–388 (2011). diagram of the progress through the phases of a non-randomised, 12. Haq, K. & McElhaney, J. E. Immunosenescence: influenza vaccination and the unblinded, observational study. elderly. Curr. Opin. Immunol. 29,38–42 (2014). 13. Nath, K. D. et al. Clinical factors associated with the humoral immune response to influenza vaccination, also known to be associated with a reduced risk of influenza vaccination in chronic obstructive pulmonary disease. Int. J. Chronic influenza infection . Seroprotection was defined as a HI titre ≥1:40, an Obstr. Pulm. Dis. 9,51–56 (2014). antibody level traditionally correlated with reduced risk of influenza 14. Gross, P. A., Quinnan, G. V., Weksler, M. E., Setia, U. & Douglas, R. G. Relation of 53,54 infection . Blood collection and sample processing are described in the chronic disease and immune response to influenza vaccine in the elderly. Vaccine Supplementary Methods. Baseline whole blood leucocyte counts were 7, 303–308 (1989). measured as standard of care. 15. Centres for Disease Control and Prevention. Influenza(Flu) Past Seasons Vaccine Effectivenes, https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates. html?web=1&wdLOR=cD4ED0E1F-CD53-4005-A613-BD4BF9FADF1A (2020). Statistical analysis 16. Gillard, P. et al. Long-term outcome of the humoral and cellular immune response of an H5N1 adjuvanted influenza vaccine in elderly persons: 2-year Descriptive statistics were calculated separately for each vaccine strain. follow-up of a randomised open-label study. Trials 15, 419 (2014). Vaccine responses were described as seroconversion and seroprotection 17. Chuaychoo, B. et al. Comparison of immunogenicity between intradermal and rates and as back-transformed GMT. Participants who did not supply blood intramuscular injections of repeated annual identical influenza virus strains post- samples at both baseline and 28 days p.i. were excluded from the analysis. pandemic (2011-2012) in COPD patients. Hum. Vaccin. Immunother. 16, A p value of <0.05 was considered to be statistically significant. Clinical 1371–1379 (2020). correlations, GLMs and regression models were generated using R (version 18. Ustinov, N. B., Zavyalova, E. G., Smirnova, I. G. & Kopylov, A. M. The power and 4.0.2, 2020, The R Foundation for Statistical Computing Platform, Vienna, limitations of influenza virus hemagglutinin assays. Biochemistry 82, Austria). Graphs were generated in R and GraphPad Prism, version 8.4.2 1234–1248 (2017). (464), (GraphPad Software, San Diego, CA, USA, www.graphpad.com). 19. Krammer, F. The human antibody response to influenza A virus infection and vaccination. Nat. Rev. Immunol. 19, 383–397 (2019). 20. Kopsaftis, Z., Wood-Baker, R. & Poole, P. Influenza vaccine for chronic obstructive Clinical study registration pulmonary disease (COPD). Cochrane Database Syst Rev. https://doi.org/10.1002/ This study is registered with Australian New Zealand Clinical Trials Registry 14651858.CD002733.pub3 (2018). (ANZCTR), under the title “Using influenza vaccination to understand and 21. Wongsurakiat, P. et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 125, improve immune responses to vaccination in patients with COPD and 2011–2020 (2004). healthy older people.” Registration number: ACTRN: ACTRN12620000830998. Published in partnership with the Sealy Institute for Vaccine Sciences npj Vaccines (2022) 8 N. Snape et al. 22. Belongia, E. A. et al. Variable influenza vaccine effectiveness by subtype: a sys- 50. Young, B. et al. Do antibody responses to the influenza vaccine persist year-round tematic review and meta-analysis of test-negative design studies. Lancet Infect. in the elderly? A systematic review and meta-analysis. Vaccine 35, 212–221 Dis. 16, 942–951 (2016). (2017). 23. Tsang, J. S. et al. Global analyses of human immune variation reveal baseline 51. Network, W. G. I. S. Manual for the Laboratory Diagnosis and Virological Surveil- predictors of postvaccination responses. Cell 157, 499–513 (2014). lance of Influenza (WHO Press, 2011). 24. Merani, S., Kuchel, G. A., Kleppinger, A. & McElhaney, J. E. Influenza vaccine-mediated 52. Beyer, W. E. P., Palache, A. M., Lüchters, G., Nauta, J. & Osterhaus, A. D. M. E. protection in older adults: Impact of influenza infection, cytomegalovirus serostatus Seroprotection rate, mean fold increase, seroconversion rate: which parameter and vaccine dosage. Exp Gerontol. https://doi.org/10.1016/j.exger.2017.09.015 (2017). adequately expresses seroresponse to influenza vaccination? Virus Res. 103, 25. Huang, K.-Y. A., Chang, S.-C., Huang, Y.-C., Chiu, C.-H. & Lin, T.-Y. Antibody 125–132 (2004). responses to trivalent inactivated influenza vaccine in health care personnel 53. Salk, J. E., Menke, W. J. Jr. & Francis, T. Jr. A clinical epidemiological and immu- previously vaccinated and vaccinated for the first time. Sci. Rep. 7, 40027 (2017). nological evaluation of vaccination against epidemic influenza. Am. J. Epidemiol. 26. Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell 42,57–93 (1945). responses to influenza. Sci. Transl. Med. 7, 316ra192 (2015). 54. Hannoun, C., Megas, F. & Piercy, J. Immunogenicity and protective efficacy of 27. Nuñez, I. A. et al. Impact of age and pre-existing influenza immune responses in influenza vaccination. Virus Res. 103, 133–138 (2004). humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza A strains. PLoS ONE 12, e0185666 (2017). 28. Nienen, M. et al. The role of pre-existing cross-reactive central memory CD4 ACKNOWLEDGEMENTS T-cells in vaccination with previously unseen influenza strains. Front. Immunol. 10, We would like to sincerely thank the participants of this study, the research nurses 593–593 (2019). and the hospitals involved in this study. We thank the funding body, National Health 29. Li, G. M. et al. Pandemic H1N1 influenza vaccine induces a recall response in & Medical Research Council (NHMRC), Australia (grant number #APP1081433), for humans that favors broadly cross-reactive memory B cells. Proc. Natl Acad. Sci. supporting this study. We also thank the reviewers for providing their time and USA 109, 9047–9052 (2012). comments to improve this manuscript. 30. Trieu, M. C. et al. Long-term maintenance of the influenza-specific cross-reactive memory CD4+ T-cell responses following repeated annual influenza vaccination. J. Infect. Dis. 215, 740–749 (2017). AUTHOR CONTRIBUTIONS 31. Hoa, L. N. M. et al. Influenza A(H1N1)pdm09 but not A(H3N2) virus infection G.P.A., J.W.U. and L.B.I. conceived and designed the experiments. N.S., A.G.J., A.C.H., induces durable sero-protection: results from the Ha Nam Cohort. J. Infect. Dis. Y.X. and T.C. performed acquisition of data and experimental analysis. N.S. and A.J. https://doi.org/10.1093/infdis/jiaa293 (2020). conducted data analysis and drafted the manuscript. N.S., A.J., A.C.H., G.P.A. and J.W. 32. Cheng, A. C. et al. Repeated vaccination does not appear to impact upon influ- U. contributed to the interpretation and critical revision of the data. A.J., J.W.U. and enza vaccine effectiveness against hospitalization with confirmed influenza. Clin. G.P.A. revised the manuscript. All authors read and approved the final manuscript. Infect. Dis. 64, 1564–1572 (2017). 33. Bartoszko, J. J. et al. Does consecutive influenza vaccination reduce protection against influenza: a systematic review and meta-analysis. Vaccine 36, 3434–3444 (2018). COMPETING INTERESTS 34. Govaert, T. E. et al. The efficacy of influenza vaccination in elderly individuals: a randomized double-blind placebo-controlled trial. JAMA 272, 1661–1665 (1994). Theauthors declarethe following financial interests/personal relationships which 35. Burel, J. G. et al. Evaluation of immune responses to influenza vaccination in may be considered as potential competing interests: J.W.U. declares: Support for chronic obstructive pulmonary disease. J. Vaccines Vaccin. S4, 001 (2012). the present manuscript from National Health & Medical Research Council 36. Kimball, J., Zhu, Y., Wyatt, D., Trabue, C. H. & Talbot, H. K. Influenza Vaccine Failure (Australia) for project grant funding to the University of Queensland. A.C.H. Associated with Age and Immunosuppression. J. Infect. Dis. https://doi.org/ declares: ACH currently works for Roche, a manufacturer of influenza antivirals. A. 10.1093/infdis/jiaa757 (2020). C.H. owns stock in Roche. A.C.H.’s involvement in the study was prior to being 37. Dalziel, B. D. et al. Urbanization and humidity shape the intensity of influenza employed by Roche. All other authors declare that they have no known conflict of epidemics in U.S. cities. Science 362, 75 (2018). interests. 38. Lowen, A. C. & Steel, J. Roles of humidity and temperature in shaping influenza seasonality. J. Virol. 88, 7692 (2014). 39. Tamerius, J. D. et al. Environmental predictors of seasonal influenza epidemics ADDITIONAL INFORMATION across temperate and tropical climates. PLoS Pathog. 9, e1003194 (2013). Supplementary information The online version contains supplementary material 40. Hart, P. H., Gorman, S. & Finlay-Jones, J. J. Modulation of the immune system by available at https://doi.org/10.1038/s41541-021-00422-4. UV radiation: more than just the effects of vitamin D? Nat. Rev. Immunol. 11, 584–596 (2011). Correspondence and requests for materials should be addressed to John W. Upham. 41. McElhaney, J. E. et al. Predictors of the antibody response to influenza vaccination in older adults with type 2 diabetes. BMJ Open Diabetes Res. Care 3, e000140 (2015). Reprints and permission information is available at http://www.nature.com/ 42. Nunzi, E., Iorio, A. M. & Camilloni, B. A 21-winter seasons retrospective study of reprints antibody response after influenza vaccination in elderly (60–85 years old) and very elderly (>85 years old) institutionalized subjects. Hum. Vaccin. Immunother. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 13, 2659–2668 (2017). in published maps and institutional affiliations. 43. Ohmit, S. E., Petrie, J. G., Cross, R. T., Johnson, E. & Monto, A. S. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J. Infect. Dis. 204, 1879–1885 (2011). 44. Crooke, S. N., Ovsyannikova, I. G., Poland, G. A. & Kennedy, R. B. Immunosenes- Open Access This article is licensed under a Creative Commons cence and human vaccine immune responses. Immun. Ageing 16, 25 (2019). Attribution 4.0 International License, which permits use, sharing, 45. Ludwig, M., Jacob, J., Basedow, F., Andersohn, F. & Walker, J. Clinical outcomes adaptation, distribution and reproduction in any medium or format, as long as you give and characteristics of patients hospitalized for Influenza or COVID-19 in Germany. appropriate credit to the original author(s) and the source, provide a link to the Creative Int J. Infect. Dis. 103, 316–322 (2021). Commons license, and indicate if changes were made. The images or other third party 46. Cates, J. et al. In Morbidity and Mortality Weekly Report Vol. 69 (ed US Department of material in this article are included in the article’s Creative Commons license, unless Health and Human Services) (Centres for Disease Control and Prevention, 2020). indicated otherwise in a credit line to the material. If material is not included in the 47. Grech, V. & Borg, M. Influenza vaccination in the COVID-19 era. Early Hum. Dev. article’s Creative Commons license and your intended use is not permitted by statutory 148, 105116 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 48. Capone, A. Simultaneous circulation of COVID-19 and flu in Italy: Potential from the copyright holder. To view a copy of this license, visit http://creativecommons. combined effects on the risk of death? Int. J. Infect. Dis. 99, 393–396 (2020). org/licenses/by/4.0/. 49. Camilloni, B. et al. An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home. Vaccine 28, 7536–7541 (2010). © The Author(s) 2022 npj Vaccines (2022) 8 Published in partnership with the Sealy Institute for Vaccine Sciences

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