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Influenza infection leads to increased morbidity and mortality in those with heart failure, and individuals with heart failure exhibit reduced antibody responses to influenza vaccine. We hypothesized that patients with heart failure randomized to double dose (DD) influenza vaccine will mount more vigorous humoral immune responses compared with those given standard dose (SD) vaccine.
We randomized 28 heart failure patients to DD (30 μg/strain) or SD (15 μg/strain) influenza vaccine. We assessed antibody production by haemagglutination inhibition assay (reported as log haemagglutination units) prior to, at 2–4 weeks and at 4–6 months following vaccination. Baseline antibody titres between DD (n = 12, mean age 64 ± 10 years) and SD (n = 16, mean age 63 ± 9 years) did not differ significantly. At 2–4 weeks, DD haemagglutination unit changes were significantly higher than those of SD (3.3 vs. 1.6 for A/H3N2, P < 0.001; 1.9 and 1.1 for A/H1N1, P = 0.009; and 1.7 and 1 for B-type, P = 0.02). At 4–6 weeks, there were no differences in titres in any of the virus types between treatment groups and, although titres decreased, levels remained above the seroprotective threshold.
Higher influenza vaccine doses may elicit increased antibody-mediated responses in patients with heart failure; further studies should assess whether clinical outcomes are improved with this strategy.
In patients with cardiovascular disease, influenza illness results more frequently in hospital admissions, longer lengths of stay, and increased mortality compared with younger, healthy individuals.1 Moreover, patients with cardiovascular disease experience the highest rate of influenza-related death compared with patients with any other chronic condition.2 Patients with heart failure are at increased risk for infection with influenza and its related complications compared with patients without heart failure.3,4 Annual vaccination has been associated with reduced cardiovascular and all-cause hospitalizations and mortality.5,6 We and others have shown that the presence and severity of heart failure were associated with reduced humoral and altered cell-mediated responses to influenza vaccine, which may potentially reduce the degree to which those with heart failure are protected by yearly vaccination.7–9
Patients with chronic conditions and individuals over age 50 receive the inactivated trivalent vaccine in the United States, whereas a live, attenuated vaccine is available for those younger than 50 and without chronic conditions. While the influenza vaccine viral strains may change from year to year, each season's vaccine traditionally includes 15 μg of antigen, or haemagglutinin (HA), each of A/H3N2, A/H1N1, and B-type viral strains (classified by virus surface antigens). A high dose vaccine containing 60 μg of HA per strain was developed for adults over age 65 years, as this group exhibits decreased immune responses to the standard dose (SD) trivalent vaccine, evidenced by lower than expected antibody titres following vaccine administration.10,11 Serum antibody levels were increased following high vaccine dose administration compared with SD.12–14 A more vigorous response has been associated with a higher degree of protection from influenza infection.15–17 Higher vaccine doses have not been studied in patients with heart failure.
The objective of this pilot study was to assess immune responses in patients with heart failure randomized to a double dose (DD) vs. an SD of influenza vaccine, and to investigate vaccine antibody titres 4–6 months following influenza vaccination between groups.
Patients with heart failure were recruited in a consecutive fashion from the University of Wisconsin Hospital Advanced Heart Disease Clinic. Patients enrolled had a diagnosis of heart failure, were stable on guideline-based heart failure therapies for at least 1 month, and had previous immunization with the influenza vaccine. Patients with contraindications to the vaccine (previous allergy to the vaccine or egg products, moderate to severe febrile illness), and those currently taking immunosuppressive therapy were excluded. The study complied with the Declaration of Helsinki. The protocol was approved by the University of Wisconsin institutional review board, and all participants provided written informed consent in accordance with established guidelines for the protection of human subjects.
This prospective, randomized, double-blind, active-controlled study enrolled patients during the 2009/2010 influenza season. Participants were randomized in a permuted block fashion, stratified by age (greater than or less than 70 years old), to receive an SD of 15 μg/strain of the 2009–2010 influenza vaccine or a DD containing 30 μg/strain administered by intramuscular injection. Phlebotomy was performed at baseline, at 2–4 weeks, and at 4–6 months following vaccination to measure antibody titres. Patients were contacted via telephone by study team members 1 week post-vaccination to assess adverse reactions to the vaccine.
Antibody responses were determined by haemagglutination inhibition assay, which measured serum influenza antibody concentrations. The haemagglutination inhibition assay was performed in duplicate using standard microtitre techniques. Briefly, influenza virus-induced agglutination of guinea pig red blood cells was inhibited by antibodies present in the human serum. Serial dilutions of the human sera were made. Titrated influenza antigen was incubated with the serum dilutions for 30 min. Guinea pig red blood cells (50 μL of 0.5% in phosphate-buffered saline) were added and incubated for 45 min. The dilution of serum that no longer inhibits HA was the influenza antibody titre.7 A protective antibody response to influenza vaccine was defined as an antibody titre ≥1:40. Seroconversion after influenza immunization was defined as a four-fold increase in antibody concentrations.18,19
Baseline characteristics were compared with χ2 or Fisher's exact test for categorical variables or t-tests for continuous variables. The primary study endpoint was the change in antibody titres from baseline to 2–4 weeks between DD and SD influenza vaccine groups. Secondary endpoints included antibody titres between groups at 4–6 months following influenza vaccination and adverse event rates between groups. A sample size of 32 participants was required to provide 80% power at the 0.05 significance level to detect a 30% difference in the antibody titre to one vaccine antigen. Seroprotection was defined as HA >1:40, and seroconversion was defined as a four-fold rise in antibody titre from baseline to at least one vaccine strain. Rates of seroprotection and seroconversion between groups were assessed with χ2 test. Antibody titres were log transformed, and changes from baseline were examined with linear regression models, adjusting for baseline antibody titres (to account for previous exposure to influenza viruses and vaccine antigens) and randomized vaccine dose.
Twenty-eight participants were enrolled in the study (Figure 1). Baseline characteristics are shown in Table 1. The majority of participants (86%) were male and 46% had an ischaemic heart failure aetiology. The mean ages of the DD and SD groups were 64 ± 10 and 63 ± 9 years, respectively. More participants in the SD group took beta-blockers (100% vs. 67%, P = 0.013). A few other numerical differences included higher use of the combination of hydralazine and isosorbide (8% and 31%, P = 0.06), use of diuretics (50% and 81%, P = 0.08), and use of digoxin in the standard dose group (8% and 63%, P = 0.07).
Seroprotection rates at 2–4 weeks did not differ between DD and SD groups (A/H3N2 100% vs. 93%, P = 0.38; A/H1N1 91% vs. 80%, P = 0.45; B-type 73% vs. 67%, P = 0.74). The rates of seroconversion were higher in the DD group compared with the SD group for the A/H3N2 strain (92% vs. 56% for A/H3N2, P = 0.04), and numerically but not significantly higher for the A/H1N1 (75% vs. 50%, P = 0.17) and the B-type strain (58% vs. 25%, P = 0.35) (Figure 2). The DD group exhibited a more pronounced change in HA units from baseline to 2–4 weeks post-vaccination compared with the SD group for all three vaccine strains (Figure 3). DD and SD HA changes from baseline (log-transformed) were 3.3 and 1.6 for A/H3N2 (P < 0.001) between DD and SD groups, 1.9 and 1.1 for A/H1N1 (P = 0.009), and 1.7 and 1 for B-type (P = 0.02). There were no significant differences in antibody responses between participants older (n = 6) or younger (n = 22) than 70 years of age, which we stratified for during randomization (data not shown).
At 4–6 months following vaccination, antibody titres were not significantly different between DD and SD groups for all three vaccine strains (Figure 4). The mean absolute log-transformed HA levels for the DD and SD groups at 4–6 months were 4.4 and 4.5 for A/H3N2, 3.3 and 2.9 for A/H1N1, and 2.5 and 2.2 for the B-type antigen. Seroprotective antibody titres remained for 77% and 87.5% of participants in the SD and DD groups, respectively (P = 0.55 for comparison between 4–6 month seroprotection rates between groups).
The rates of adverse events in this study were low. The most common adverse event was injection site soreness, which occurred in three individuals per group. Two participants in the DD group experienced severe soreness. One participant in the SD group experienced muscle aches (Table 2).
This pilot study compared humoral immune responses in patients with heart failure randomized to a DD vs. a SD of trivalent inactivated influenza vaccine. Rates of seroconversion were significantly higher with the DD vaccine dose for the A/H3N2 vaccine antigen, and antibody titres were significantly higher for all three antigens compared with SD vaccine 2–4 weeks post-vaccination. After 4–6 months, we noted similar antibody titres between DD and SD groups, which remained at seroprotective levels for the majority of participants.
Our findings of higher initial antibody titres in response to a DD of influenza vaccine in patients with heart failure are consistent with other studies in older adults examining higher vaccine doses ranging from 30 to 60 µg of HA per vaccine strain.12–14,20 Older adults have exhibited lower humoral immune responses to influenza vaccination compared with younger individuals. As such, a high dose of trivalent, inactivated vaccine is available in patients over the age of 65, although current recommendations do not advocate for or against this strategy. Another alternative vaccine regimen is a booster vaccine dose, but resulting antibody titre levels and T-cell responses have been mixed in randomized studies using this approach.21–23 An important question is whether higher antibody titres are associated with improved clinical outcomes. Although we do not have data on clinical outcomes in our pilot study, previous investigators have shown that higher initial antibody titres conferred better vaccine-induced protection from influenza infection, suggesting that this strategy might lead to improved outcomes in heart failure patients.15,24 However, until more definitive outcome data are available with a higher dose vaccine in patients with heart failure, this approach should not be uniformly applied.
We noted that participants randomized to DD influenza vaccine had similar antibody titres to those given SD vaccine when measured 4–6 months after vaccine administration. The clinical implications of these particular findings are unknown. A review of 14 studies published on the persistence of antibody titre levels for ≥4 months post-influenza vaccination in older adults concluded that while antibody titres wane during the influenza season, protective thresholds of 1:40 were maintained against at least one influenza vaccine antigen at >4 months post-vaccination.25 Our results were similar with respect to maintenance of seroprotective levels 4–6 months post-vaccination. Nonetheless, initial titres 2–4 weeks post-vaccination have been shown to correspond to vaccine-induced protection from infection, while the association between peak season titres and outcomes is not well established.
Our study had several limitations. First, the sample size is small with limited power to detect differences in immune responses between groups. Additionally, due to difficulty recruiting following the A/H1N1 ‘swine flu’ pandemic during the 2009/2010 influenza season, enrolment did not meet the pre-specified 32 participants. We were unable to examine the influenza infection rates between groups, as the study was not powered to do so; this endpoint is of greater significance than antibody titres. We compared only DD vaccines with SD; higher doses may result in more pronounced differences in seroprotection and seroconversion rates in addition to sustained titres 4–6 months post-vaccination, unlike what we saw in our study. Adverse event rates were low, but, due to our small sample size, we cannot dismiss the possibility that higher vaccine doses may result in differing tolerability and higher rates of adverse events. Finally, while both humoral and cell-mediated immune responses are important for conferring vaccine-induced protection, this study only assessed humoral responses.
In summary, patients with heart failure randomized to a DD of influenza vaccine exhibited higher initial antibody titres to A/H3N2, A/H1N1, and B-type antigens. At 4–6 months post-vaccination, absolute antibody titres were similar between DD and SD groups but well above seroprotective levels. These findings suggest that higher doses of influenza vaccine might be more protective in heart failure patients, and should be further evaluated in larger randomized outcomes trials.
The authors gratefully acknowledge the patients who participated in this study.
The National Institutes of Health [1KL2RR025012-01].
Conflicts of interest: none declared.