ABSTRACT
Lung cancer is a leading cause of cancer-related death, and patients with lung cancer are a priority group for influenza vaccination. However, few studies have assessed the immunogenicity of the influenza vaccine in these patients. Here, we performed a prospective study to evaluate the immunogenicity of the influenza vaccine in patients with lung cancer undergoing anticancer chemotherapy. Twenty-five patients with lung cancer undergoing anticancer chemotherapy and 26 patients with chronic obstructive pulmonary disease (COPD) as controls were enrolled. A trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Texas/50/2012 (H3N2), and B/Massachusetts/2/2012 was administered as a single subcutaneous injection. Serum samples were collected before vaccination, and at 4–6 weeks after vaccination. Levels of serum antibody to hemagglutinin were measured. Among patients with lung cancer, the seroprotection rate (postvaccination titer > 1:40) was 84% for both A(H1N1) and A(H3N2), similar to the levels observed in patients with COPD. However, the seroprotection rate for the B strain was significantly lower in patients with lung cancer than in patients with COPD (64% versus 92%). Even after adjustment for potential confounders, patients with lung cancer had a significantly lower odds ratio for seroprotection against the B strain than patients with COPD. Moreover, in patients with lung cancer, those receiving the platinum doublet treatment tended to exhibit a lower seroprotection rate than those receiving a single agent. Thus, patients with lung cancer undergoing anticancer chemotherapy showed acceptable immune responses to a trivalent influenza vaccine, supporting the recommendation for annual influenza vaccination in these patients.
Introduction
Patients with cancer undergoing systemic chemotherapy have a significant risk of morbidity and mortality from influenza infection.Citation1,2 According to a previous report,Citation1 the mortality rate for influenza infection is approximately 9% among patients with cancer. In addition, influenza infection and influenza-related complications often prevent consecutive courses of chemotherapy and worsen the prognosis of these patients.Citation1,3,4 Therefore, annual influenza vaccination is recommended in patients with cancer for the prevention of severe influenza or related bacterial infections.Citation2,5,6 Despite this recommendation, prior studies have reported low influenza vaccination rates among patients receiving chemotherapy for cancer.Citation7,8 The main reasons for the absence of vaccination include lack of recommendation by the treating physician (72%), fear of side effects (33%), and concerns regarding vaccination efficacy (10%).Citation7 Moreover, information concerning influenza vaccine efficacy, safety, and optimal timing in patients with cancer is limited.Citation3 However, the immunogenicity of influenza vaccination in cancer patients has been reported in several studies.Citation3 The reported seroprotection rates (sPs; postvaccination titer > 1:40) of the inactivated influenza vaccine in patients with solid cancers ranges from 38%–78%.Citation9-11 The intensity and type of chemotherapy and the timing of vaccination in the course of chemotherapy influence the immunogenicity of influenza vaccination.Citation3
Lung cancer is the leading cause of cancer-related death among men and women.Citation12 Owing to the high incidence of lung cancer worldwide, influenza vaccination for this group of patients is crucial. However, to our knowledge, only one study, performed in 1999, has assessed the immunogenicity of influenza vaccine in patients with lung cancer.Citation9 In addition, in the last few years, the intensity of anticancer chemotherapy has changed with the development and introduction of new drugs such as platinum agents, third-generation drugs, pemetrexed, and bevacizumab.Citation13
Therefore, in this study, we aimed to evaluate the immunogenicity of the influenza vaccine in patients with lung cancer undergoing anticancer chemotherapy compared with that in patients with chronic obstructive disease (COPD) as an immunocompetent control. The study subjects were recruited from the Kameda Medical Center, a tertiary care and teaching hospital, which has 925 inpatient beds, 34 clinical departments, and 3000 medical staffs. The Kameda Medical Center covers the southern area of Chiba, Japan, which has a population of ∼1,000,000. Since immunoresponses are influenced by prevaccination titers, which are related to previous virus exposure (through infection or vaccination), we used logistic regression to analyze models that include potential confounders, including prevaccination titer, as explanatory variables.
Results
A total of 25 patients with lung cancer and 27 patients with COPD were eligible for this study. All patients received one dose of the trivalent influenza vaccine between November and December 2013. Serum samples at 4–6 weeks after vaccination were collected from 25 patients with lung cancer and 26 patients with COPD. One patient with COPD showed a mild rash within 48 h after vaccination, and no other severe adverse events occurred in any of the patients with lung cancer or COPD. During the study period, no subjects reported laboratory-confirmed influenza or influenza-like illness (defined by acute febrile illness [temperature > 38.0°C] with one or more respiratory symptoms [nasal discharge, sore throat, or cough]).
The characteristics of the 51 patients included in the immunogenicity analyses are shown in . The mean age was 69.4 years, and 41 patients (80.4%) were men. The proportions of patients with pretiter levels of 1:10 or more ranged from 48%–68% in patients with lung cancer and from 69%–88% in patients with COPD. For the A/California/7/2009 (H1N1) pdm09 strain, the percentage of patients with pretiter levels of 1:10 or more was significantly higher in patients with COPD than that in patients with lung cancer. Adenocarcinoma was the most common histological type in patients with lung cancer (40%). Fifteen (60%) patients received chemotherapy with platinum doublet treatment, and 10 (40%) patients received chemotherapy with a single agent.
Table 1. Characteristics of patients with lung cancer or COPD.
shows the immune responses to the trivalent influenza vaccination among patients with lung cancer or COPD. Patients with lung cancer showed significantly lower geometric mean titers (GMTs) for A/California/7/2009 (H1N1) pdm09 before vaccination than patients with COPD. In the other 2 strains, patients with lung cancer tended to show lower GMTs before vaccination than patients with COPD did. In all strains, GMTs reached the protection levels (≥1:40), and the mean fold rise (MFR) values were over 2.0 fold. The sPs and seroresponse rates (sRs) in patients with lung cancer were 64%–84% and 60%–72%, respectively. In the A/California/7/2009 (H1N1) pdm09 and A/Texas/50/2012 (H3N2) strains, there were no significant differences in sPs between patients with lung cancer and those with COPD. However, the sP of B/Massachusetts/02/2012 in patients with lung cancer was significantly lower than that in patients with COPD (64% vs. 92%, respectively; p = 0.019). In all strains, sRs were not significantly different between patients with lung cancer and patients with COPD.
Table 2. Immune responses to the trivalent influenza vaccine in patients with lung cancer or COPD.
shows the odds ratios (ORs) for sRs after trivalent influenza vaccination in patients with lung cancer compared with those in patients with COPD. In all strains, there were no significant reductions in ORs in patients with lung cancer compared with that in patients with COPD, in both the crude analysis and multivariate analysis.
Table 3. Odds ratios for seroresponse rates at after trivalent influenza vaccination in patients with lung cancer or COPD.
shows ORs for seroconversion reats (sCs) after trivalent influenza vaccination in patients with lung cancer compared with those in patients with COPD. For all strains, based on ORs, there were no significant differences between patients with lung cancer and patients with COPD in the multivariate analysis.
Table 4. Odds ratios for seroconversion rates after trivalent influenza vaccination in patients with lung cancer or COPD.
shows ORs for sPs after trivalent influenza vaccination in patients with lung cancer compared with those in patients with COPD. In B/Massachusetts/02/2012, patients with lung cancer had a significantly lower OR for sP than patients with COPD (p = 0.028) in the multivariate analysis. For the other 2 strains, the ORs for sPs were not significantly different between the 2 patient groups.
Table 5. Odds ratios for seroprotection rates at after trivalent influenza vaccination in patients with lung cancer or COPD.
shows the immune responses to trivalent influenza vaccination among patients with lung cancer undergoing anticancer chemotherapy. For A/Texas/50/2012(H3N2), the MFR was 3.6 in patients receiving platinum doublet treatment; this was significantly lower than that in patients receiving treatment with a single agent (11.3; p = 0.049). The sPs were lower in patients receiving platinum doublet treatment, although these differences were not significant, for A/California/7/2009 (H1N1) pdm09 (platinum doublet treatment versus single agent treatment: 73% vs. 100%; p = 0.125), A/Texas/50/2012 (H3N2) (platinum doublet treatment versus single agent treatment: 73% vs. 100%; p = 0.125), and B/Massachusetts/02/2012 (platinum doublet treatment versus single agent treatment: 60% vs. 70%; p = 0.691).
Table 6. Immune response to the trivalent influenza vaccine in patients with lung cancer, according to the type of chemotherapy.
Discussion
In this study, we showed that influenza vaccination induced sufficient immune responses in both patients with COPD and those with lung cancer. The immunity after vaccination satisfied the international licensing criteria of the European Agency for the Evaluation of Medical Products and the US Food and Drug Administration.Citation14,15 For the A/California/7/2009 (H1N1) pdm09 and A/Texas/50/2012 (H3N2) strains, there were no significant differences in the ORs for sP, sR, or sC between patients with COPD and those with lung cancer in the multivariate analysis. However, the OR for the sP of B/Massachusetts/02/2012 was significantly reduced in patients with lung cancer in the multivariate analysis. In addition, the sP, sR, and sC tended to be lower in patients receiving platinum doublet treatment than in patients receiving single agent treatment. Thus, platinum doublet chemotherapy is considered a high-intensity treatment and may suppress the ability of the immune system to make anti-influenza antibodies.
Oncology patients are heterogeneous, and the immunogenicity of the influenza vaccine in patients with cancer differs depending on the type of cancer and the intensity of chemotherapy.Citation3,16 Some studies have shown that immunization with the influenza vaccine has no benefit in providing adequate seroconversion, particularly in patients with hematological diseases such as lymphomas and multiple myeloma.Citation17-20 Nevertheless, other studies examining the immunogenicity of vaccination in hematological disease have reported adequate immunoresponses.Citation21,22 In addition, positive data have been obtained in the majority of studies assessing the immunogenicity of the influenza vaccine in patients with solid tumors such as breast cancer, colorectal cancer, and lung cancer.Citation9,10,23,24 Although the observed immunogenicity in patients with solid tumors undergoing chemotherapy has been shown to reach protective levels,Citation9-11,23-25 some reports have shown that the immunogenicity induced by vaccination is lower than that in immunocompetent controls.Citation10,23 A previous study assessing the immunogenicity of the influenza vaccine in patients with lung cancer showed an sP of 78% (postvaccination titer > 1:40), similar to the seroprotection level of 64%–84% in our study.Citation9
In the present study, the sP of B/Massachusetts/02/2012 in patients with lung cancer was 64%, which was significantly lower than that for patients with COPD and was relatively low in comparison with that of the other 2 strains in patients with lung cancer. A previous report showed increased sensitivity and reduced specificity of hemagglutination inhibition tests with an ether-treated influenza B strain.Citation26 In our study, none of the 3 strains was treated with ether. Hence, we believe that the differences in sPs among strains were not derived from variations in methodology. Concerning this relatively poor immune response to B/Massachusetts/02/2012 in patients with lung cancer, our results were similar to those of a prior study, in which the immunogenicity of an inactive quadrivalent influenza vaccine containing the B/Massachusetts/02/2012 strain was evaluated.Citation27 It is possible that pre-existing immunity to B strains other than B/Massachusetts/02/2012 negatively affected the immune response to the B/Massachusetts/02/2012 strain; this phenomenon is called original antigenic sin.Citation28,29 For example, a previous study assessing the prime-boost responses following a change in the 2 B lineages (B/Yamagata and B/Victoria) reported the influence of original antigenic sin on responses to B strains; repeated administration of the annual trivalent influenza vaccine containing the B/Victoria lineage antigen strongly recalled antibodies to the B/Yamagata antigen after the first exposure, but elicited lower B/Victoria responses.Citation30 In Japan, a mixed epidemic of B/Victoria and B/Yamagata was observed during the 2011/2012 and 2012/2013 seasons.Citation31 During these seasons, some participants in our study could have been sensitized to the B/Victoria or B/Yamagata strain, thereby decreasing immunogenicity to B/Massachusetts/02/2012 (B/Yamagata lineage) owing to the influence of original antigenic sin on responses to B strains. Moreover, the lower prevaccination antibody titer in patients with lung cancer may explain the decreased sP. In the present study, most of the patients with lung cancer had received repetitive chemotherapy at the time of vaccination, potentially strengthening the lower GMTs before vaccination owing to the immunosuppression caused by chemotherapy.
In this study, we chose patients with COPD as the immunocompetent control group because they are also a priority group for influenza vaccination,Citation32,33 and are considered immunocompetent compared to patients with cancer undergoing chemotherapy. However, whether patients with COPD are suitable as a control group may be controversial because there is insufficient high-quality evidence on current influenza vaccine regimens for patients with COPD.Citation34 In a prior study, patients with COPD and healthy controls obtained seroprotective levels of antibodies after influenza vaccination, although the sR seemed to be lower in patients with COPD than in healthy participants, because of the higher prevaccination titer in patients with COPD.Citation35 In addition, our study showed that the sPs among patients with COPD reached 81%–96% after vaccination. Thus, the patients with COPD in our study appeared to be appropriate as a control group.
Our study has several limitations. First, we had a relatively small sample size. Enrollment of patients was restricted by the short period from the time when the influenza vaccine became available to vaccination before the anticipated winter outbreak of influenza infection. Inclusion of more cases may provide more definitive results, particularly when considering the effects of different chemotherapy regimens on patients with lung cancer. Second, in our study, there was the possibility of intercurrent asymptomatic infections. However, we monitored all patients for influenza-like illness, and no patients experienced confirmed influenza virus infections during the study period. Thus, we believe that the effect of intercurrent infection was not large enough to invalidate the present results. Third, healthy controls were not evaluated in this study. However, we evaluated patients with COPD as a immunocompetent control group; these patients were considered appropriate based on their high sPs. Fourth, the antibody titers at the end of season were not evaluated in the present study because we wanted to focus on the antibody titers before vaccination and at 4–6 weeks after vaccination. We thought that the immunogenicity at 4–6 weeks after vaccination was clinically important for evaluating the immunoprotective ability against influenza infection during the influenza season.
In conclusion, patients with lung cancer undergoing chemotherapy showed an acceptable immune response to the trivalent influenza vaccine without significant adverse effects, supporting the recommendation for annual influenza vaccination in patients with lung cancer. Further studies assessing influenza vaccine efficacy in patients with cancer are needed to strengthen the evidence supporting influenza vaccination in these patients.
Materials and methods
Study design and patients
In November and December 2013, patients with lung cancer undergoing chemotherapy and patients with COPD being treated at the Department of Pulmonary Medicine, Kameda Medical Center, Chiba, Japan were invited to participate in this study. We chose patients with COPD as immunocompetent controls because these patients are a priority group for influenza vaccination,Citation32,33 and most patients with COPD receive the influenza vaccine annually in Japan.
The inclusion criteria were as follows: 1) patients with lung cancer who underwent anticancer chemotherapy with cytotoxic agents from 2 weeks before influenza vaccination to 4 weeks after vaccination, or 2) patients with COPD diagnosed based on a postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1 /FVC) of less than 70%.Citation36 Exclusion criteria were as follows: a history of influenza infection, an acute febrile illness or evidences of severe acute illness at the time of vaccination, a history of allergy due to vaccine components, or other contraindications for receiving the vaccine.
All patients provided written informed consent after the nature and possible consequences of the study were explained. The study protocol was approved by the Research Ethics Committee of the Kameda Medical Center (No. 13–061) and was performed in accordance with the Declaration of Helsinki. After obtaining informed consent, the baseline patient characteristics, including age, gender, histological type of lung cancer, clinical stage of lung cancer, stage of COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria,Citation33,36 smoking status, and type of chemotherapy, were collected.
Vaccination
FLUBIK HA Syringe (Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan) containing inactivated A/California/7/2009 (H1N1) pdm09, A/Texas/50/2012 (H3N2), and B/ Massachusetts/2/2012 (B/Yamagata lineage) was administered as a single subcutaneous injection, the typical administration route used in Japan. Each vaccine contained 15 μg hemagglutinin antigen of each strain. The vaccine did not contain thimerosal. The vaccine was prepared in embryonated chicken eggs using standard methods for the production of trivalent inactivated vaccine. Attending physicians monitored all patients until April 2014 and evaluated the occurrence of side effects from the vaccine or of influenza infection.
Measurement of antibody titers
Serum samples were collected before vaccination (S0) and at 4–6 weeks after vaccination (S1). All serum specimens were kept at −40°C until analysis. Serum antibody levels to hemagglutinin were measured according to the standard microtiter hemagglutination inhibition methodCitation37 with the same antigens as used in the vaccine. During the measurement process, none of the 3 antigens was treated with ether. All samples were assayed at the Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan in June 2014.
Statistical analyses
The following outcomes were calculated to evaluate the immunogenicity of influenza vaccine: GMT, MFR, sP (postvaccination titer > 1:40), and sR (> 4-fold rise), sC (a prevaccination titer < 1:10 and a postvaccination titer ≥ 1:40 or a prevaccination titer ≥ 1:10 and a minimum 4-fold rise in postvaccination titer). During data processing, titers of less than 1:10 were regarded as 1:5, and reciprocal antibody titers were analyzed after logarithmic transformation. The results are presented in the original scale by calculating the antilogarithm. Stratified analyses were performed to examine the effects of the following potential confounders: age at vaccination (<69 and ≥69 years), gender (men versus women), prevaccination titer (<1:10 and ≥1:10), and underlying diseases (lung cancer and COPD). The significance of fold rise within a category was assessed by the Wilcoxon signed-rank test, and intercategory comparisons were made by the Wilcoxon rank-sum test. Student's t tests or Fisher's exact tests were performed where appropriate. In addition, the independent effects of potential confounders on antibody induction were assessed by logistic regression. The models were constructed with sP, sR, and sC as the dependent variables and with the above-mentioned potential confounders as the explanatory variables. ORs and 95% confidence intervals (CIs) were calculated. All tests were 2-sided, and all analyses were performed using R version 3.2.3 (R foundation for Statistical Computing; http://www.r-project.org). Differences with p values less than 0.05 were considered significant.
Abbreviations
| COPD | = | chronic obstructive pulmonary disease |
| sP | = | seroprotection rate |
| GMT | = | geometric mean titer |
| MFR | = | mean fold rise |
| sR | = | seroresponse rate |
| OR | = | odds ratio |
| 95% CI | = | 95% confidence interval |
Disclosure of potential conflicts of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
We would like to thank Ayumu Otsuki (Department of Pulmonary Medicine, Kameda Medical Center) and Motohisa Takai (Department of Pulmonary Medicine, Kameda Medical Center) for assistance with this study.
Funding
This study was supported by a research grant for Research on Emerging and Re-emerging Infectious Diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare, Japan (H23-SHINKO-IPPAN-017).
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