Pneumococcal vaccination (13-valent pneumococcal conjugate vaccine [PCV13]) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies.
We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating 2 weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against
Of the 92 patients who underwent randomization, 43 patients in arm A (vaccination 2 weeks before chemotherapy) and 44 patients in arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > 4-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments.
The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation.
Pneumococcal vaccination is recommended for cancer patients who undergo systemic chemotherapy due to the possibility of immunosuppression and consequent risk of invasive pneumococcal disease. The latest guideline from the Infectious Diseases Society of America (IDSA) states that patients in this group should receive the sequential 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) immunization [
The immunogenicity of pneumococcal vaccines in cancer patients was shown in previous studies performed with PPSV23, which demonstrated that adequate immune responses could be induced in patients undergoing chemotherapy [
There is insufficient evidence to conclude an optimal time interval between vaccine administration and chemotherapy. However, a recent study performed with influenza vaccines in cancer patients reported that the overall antibody response did not differ significantly when vaccination was performed early (day 5) or late (day 16) during a 3-week chemotherapy cycle in breast and colon cancer patients [
In light of these previous studies, we hypothesized that administering PCV13 on the first day of chemotherapy would be as effective as vaccinating 2 weeks prior to treatment initiation. As gastric and colorectal cancers are prevalent in Korea and share similar chemotherapeutic adjuvant therapy regimens, we designed a non-inferiority trial in these patients to validate our hypothesis.
This study was a prospective randomized controlled non-inferiority trial conducted in three cancer centers in Korea from March 2016 to March 2018. The primary study objective was to evaluate whether the immunogenicity of PCV13 given on the first day of adjuvant chemotherapy is non-inferior to vaccinating 2 weeks prior to chemotherapy initiation. Patients were randomly assigned to receive PCV13 either 2 weeks before (day –14) or on the day of (day 0) the start of adjuvant chemotherapy by block randomization. Venous blood samples (10 mL) were collected on day 0 and on postvaccination day 28±7 to assess the immunogenicity of PCV-13.
Study subjects (aged ≥ 19 years) were deemed eligible if they had undergone surgical resection for primary gastric or colorectal cancer, were scheduled for adjuvant chemotherapy (fluoropyrimidine±oxaliplatin), had an Eastern Cooperative Oncology Group performance status ≤ 2, and showed adequate hematological, renal, and hepatic function within 2 weeks of randomization using the following criteria: absolute neutrophil count ≥ 1,500/mm3, platelet count ≥ 100,000/mm3, serum creatinine ≤ 1.5-fold the upper limit of normal (ULN) or estimated glomerular filtration rate > 50 mL/min calculated using the Cockcroft-Gault equation, serum aspartate aminotransferase and alanine aminotransferase ≤ 3-fold the ULN, and total bilirubin ≤ 2-fold the ULN. Exclusion criteria included previous pneumococcal vaccination, hypersensitivity to diphtheria toxin or other compounds contained in the vaccine, history of immunodeficiency disorders or autoimmune diseases, use of immunomodulatory drugs within 3 months of randomization, and signs of infection within 24 hours of vaccination.
The PCV13 (Prevenar-13, Wyeth Pharmaceuticals, Madison, NJ) contains capsular antigens of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F of
The primary endpoint was serotype-specific seroprotection after PCV13 administration. Based on historical data, the seroprotection rate of PCV13 was assumed to be 85% [
Multiplex opsonophagocytic killing assays (MOPAs) for serotypes 5, 6B, 18C, and 19A were performed on collected serum samples. Four serotypes were selected based on the nasopharyngeal carriage rate and invasive disease potential according to the serotype-specific capsular structure and thickness, which might also affect the immunogenicity [
All statistical analyses were performed using SPSS for Windows ver. 20.0 (IBM Corp., Armonk, NY). Descriptive statistics were reported as numbers and percentages of patients. OPA titers were expressed as geometric means with 95% confidence intervals (CIs). Geometric mean titers (GMTs) and their mean fold increases were analyzed using Student’s t test. Categorical variables were analyzed using the chi-squared test (Fisher exact test). A two-sided p-value < 0.05 was considered to indicate statistical significance.
This study was approved by the institutional review board of Chonnam National University Hwasun Hospital (IRB No. CNUHH-2015-126) and registered at the Clinical Research Information Service (registration No. KCT0003379). This study was conducted in concordance with the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent.
In total, 92 patients were assessed for eligibility and randomly assigned to either arm A, with PCV13 administration 2 weeks before starting adjuvant chemotherapy, or arm B, with PCV13 administration on the first day of adjuvant chemotherapy. Eighty-seven patients (arm A, n=43; arm B, n=44) were included in the final assessment of immunogenicity (
The geometric mean post-vaccination titer (GMT) of OPA with 95% CIs has been suggested to be an appropriate parameter for antibody response, accounting for its skewed distribution [
In subgroup analyses, the GMT results and mean fold increases in OPA titers were stratified by cancer type (gastric cancer vs. colorectal cancer) and chemotherapeutic regimen (fluoropyrimidine vs. fluoropyrimidine+oxaliplatin). When stratified by cancer type, pre- and post-vaccination GMTs did not differ significantly among all four serotypes between the two study arms for the two types of cancers (
Antibody levels above a certain threshold should provide adequate protection towards targeted strains. Therefore, the proportion of patients who actually reach this state of protection, known as the seroprotection rate, may be interpreted as a clinical parameter of immunogenicity. An OPA titer of 1:64 has been suggested as a threshold for evaluating an adequate response to pneumococcal vaccination [
When analyzed by subgroup, seroprotection rates were generally high in both study arms for all four serotypes, regardless of cancer type (
The high seroprotection rate in our cohort was in part due to the high titers prior to vaccination for serotypes 6B and 19A. However, the seroprotection rates in the two arms before vaccination did not differ significantly among the four serotypes (
Another way to assess immunogenicity is to analyze the percentage of patients whose post-vaccination OPA titers increase greater than four-fold compared to the pre-vaccination level, which is otherwise known as the seroconversion rate [
When stratified by cancer type, the seroconversion rates in arms A and B were similar for both cancer types. In gastric cancer, arm B had higher rates than arm A for serotypes 6B, 18C, and 19A, although these differences were not statistically significant (
Neutropenia is one of the most common adverse events of cytotoxic chemotherapy and it reflects the severity of bone marrow suppression. Therefore, we aimed to see whether the serologic responses to PCV13 were attenuated in patients whom neutropenia had occurred during the period of serum sampling. There were 20 patients who had neutropenia during the study period. Most of them were grade 1 or 2, and two patients had grade 3 neutropenia (based on Common Terminology Criteria for Adverse Events [CTCAE], ver. 5.0). We subclassified the study participants (control [n=67] vs. neutropenia [n=20]) and compared the immunogenicity assessments between the two groups. The GMT and foldincreases of titers, seroprotection, and seroconversion rates were all comparable between the two groups without statistical significance (
Chemotherapy doses are frequently modified based on the patients’ general condition or tolerability. We also assessed whether reduced-dose of chemotherapy affects the serologic responses to vaccination. In our cohort, chemotherapy doses were reduced in 45 patients and all of them were reduced to 80% of the standard regimen during the study period. We again subclassified the patients into two groups (full-dose [n=42] vs. reduced-dose [n=45]) and compared the immunogenicity parameters. No significant differences were seen in GMT and fold-increases, seroprotection, and seroconversion rates between the two groups (
In our dataset, CAPOX was the most commonly used regimen in both study arms. To analyze the immunogenicity in the background of a single regimen, we also compared the immunogenicity in patients who underwent chemotherapy with CAPOX for gastric or colorectal cancer. The geometric mean and fold increases, seroprotection, and seroconversion rates were mostly similar between the two groups (
During the study, adverse events were reported on the day of vaccine administration, and 28-day post-vaccination. Six events were reported in am A and five were reported in arm B which were all either grade 1 or 2 based on CTCAE ver. 5.0 (
This study demonstrated that administering PCV13 on the first day of adjuvant chemotherapy in patients with gastric or colorectal cancer is not inferior to administering the vaccine 2 weeks prior to chemotherapy. To the best of our knowledge, this is the first study to assess the immunogenicity of PCV13 in cancer patients undergoing systemic chemotherapy. Guidelines that recommend a ≥ 2-week interval between vaccination and chemotherapy stem mainly from limited studies performed with polysaccharide vaccines or PCV7 in patients with hematologic malignancies [
In this study, we assessed immunogenicity by analyzing the pre- and post-vaccination MOPA results from serum samples. Pre- and post-vaccination seroprotection and seroconversion rates in the two study arms were similar. However, these findings are inconsistent with pneumococcal vaccination studies performed for hematologic malignancies, which favored a ≥ 2-week interval between vaccine administration and initiation of chemotherapy [
This study has several limitations. First, we tested only four of the 13 serotypes covered by PCV13 using immunogenicity assays. Although our results consistently showed comparable immune responses for all four tested serotypes assessed using various methods, larger studies testing all serotypes are warranted. Additionally, this study included only patients undergoing adjuvant chemotherapy for gastric or colorectal cancer. It is unclear whether the results would be similar for other types of cancers treated with different chemotherapeutic regimens, or in more advanced stages requiring palliative therapies.
Despite these limitations, this study provides clear evidence that administering PCV13 on the first day of adjuvant chemotherapy is not inferior to vaccinating 2 weeks prior to starting chemotherapy in gastric and colorectal cancer patients. Further prospective trials with larger samples testing all serotypes covered with PCV13 are necessary to confirm whether this can be generalized to larger populations.
Supplementary materials are available at Cancer Research and Treatment website (
Geometric mean titers (GMTs) of opsonophagocytic activity (OPA) stratified by cancer type
Geometric mean titers (GMTs) of opsonophagocytic activity (OPA) stratified by chemotherapeutic regimen
Fold increase of post-vaccination GMTs, stratified by cancer type
Fold increase of post-vaccination GMTs, stratified by chemotherapeutic regimen
Seroprotection rates between the two study arms after vaccination
Seroprotection rates stratified by cancer type
Seroprotection rates in subgroups. Seroprotection rates, defined as the percentage of patients with opsonophagocytic activity (OPA) titers greater than 1:64, in the two study arms, stratified by (A) cancer type and (B) chemotherapeutic regimen.
Seroprotection rates stratified by chemotherapeutic regimen
Seroprotection rates prior to vaccination
Pre-vaccination seroprotection rates. Seroprotection rates in the two study arms prior to vaccination for serotypes 5, 6B, 18C, and 19A.
Seroconversion rates between the two study arms after vaccination
Seroconversion rates stratified by cancer type
Seroconversion rates in subgroups. Seroconversion rates, defined as the percentage of patients with greater than a four-fold increase in opsonophagocytic activity (OPA) titers, in the two study arms, stratified by cancer type (A) and chemotherapeutic regimen (B).
Seroconversion rates stratified by chemotherapeutic regimen
Geometric mean titers (GMTs) of opsonophagocytic activity stratified by the occurrence of neutropenia (control, n=67; neutropenia, n=20)
Fold increase of post-vaccination geometric mean titers (GMTs) stratified by the occurrence of neutropenia
Seroprotection rates between the subgroups stratified by the occurrence of neutropenia
Seroconversion rates between the subgroups stratified by the occurrence of neutropenia
Geometric mean titers (GMTs) of opsonophagocytic activity (OPA) stratified by dose of chemotherapy (full dose, n=42; reduced, n=45)
Fold increase of post-vaccination geometric mean titers (GMTs) stratified by dose of chemotherapy
Seroprotection rates between the subgroups stratified by dose of chemotherapy
Seroconversion rates between the subgroups stratified by dose of chemotherapy
Geometric mean titers (GMTs) of opsonophagocytic activity (OPA) in patients who underwent chemotherapy with CAPOX regimen (n=38)
Fold increase of post-vaccination geometric mean titers (GMTs) in patients who underwent chemotherapy with CAPOX regimen (n=38)
Seroprotection rates between the two study arms in patients who underwent chemotherapy with CAPOX regimen (n=38)
Seroconversion rates between the two study arms in patients who underwent chemotherapy with CAPOX regimen (n=38)
Adverse events. Adverse events were classified and graded according to the Common Terminology Criteria for Adverse Events ver. 5.0
Conflict of interest relevant to this article was not reported.
We wish to thank all the participants of this study. We are grateful to Korean Cancer Study Group (KCSG), Jang HC and Oh IJ for the collaborative advice. We thank the Song JY’s laboratory staff for the support during laboratory experiments.
Study diagram.
Seroprotection and seroconversion rates between the two study arms. Bar plots for the seroprotection (A) and seroconversion (B) rates of the two study arms for serotypes 5, 6B, 18C, and 19A.
Baseline characteristics of gastric and colorectal cancer patients
Characteristic | Arm A | Arm B | p-value |
---|---|---|---|
43 | 44 | ||
Male | 24 (55.8) | 28 (63.6) | 0.516 |
Female | 19 (44.2) | 16 (36.4) | |
59.9 (42.0-77.6) | 59.1 (29.1-78.9) | 0.678 | |
Gastric cancer | 10 (23.3) | 7 (15.9) | 0.429 |
Colorectal cancer | 33 (76.7) | 37 (84.1) | |
Fluoropyrimidine |
16 (37.2) | 9 (20.5) | 0.101 |
5-FU/leucovorin | 2 | 2 | |
Capecitabine | 10 | 6 | |
S-1 | 4 | 1 | |
Fluoropyrimidine+Oxaliplatin |
27 (62.8) | 35 (79.5) | |
FOLFOX | 10 | 14 | |
CAPOX | 17 | 21 |
Values are presented as number (%) unless otherwise indicated.
Fluoropyrimidine regimens include 5-fluorouracil/leucovorin, capecitabine, or S-1,
Fluoropyrimidine+oxaliplatin regimens include FOLFOX or CAPOX.
GMTs of opsonophagocytic activity
Serotype | Arm | Pre-vaccination |
Post-vaccination |
||||
---|---|---|---|---|---|---|---|
GMT | 95% CI | p-value | GMT | 95% CI | p-value | ||
5 | A | 5 | 3-7 | 0.928 | 338 | 167-693 | 0.712 |
B | 5 | 3-7 | 405 | 210-741 | |||
6B | A | 521 | 185-1,288 | 0.958 | 8,913 | 5,858-12,966 | 0.712 |
B | 505 | 252-1,022 | 10,495 | 7,920-13,341 | |||
18C | A | 100 | 53-195 | 0.935 | 4,280 | 2,659-6,631 | 0.673 |
B | 104 | 52-798 | 4,955 | 2,760-7,943 | |||
19A | A | 436 | 224-824 | 0.439 | 7,586 | 4,365-11,382 | 0.766 |
B | 308 | 176-529 | 6,947 | 4,879-9,456 |
Pre- and post-vaccination geometric mean titers (GMTs) of opsonophagocytic activity with 95% confidence intervals (CIs) in the two study arms for serotypes 5, 6B, 18C, and 19A.
Fold increase of post-vaccination geometric mean titers
Serotype | Arm A (n=43) |
Arm B (n=44) |
p-value | ||
---|---|---|---|---|---|
Geometric mean fold increase | 95% CI | Geometric mean fold increase | 95% CI | ||
5 | 72.15 | 35.93-144.86 | 88.60 | 47.55-165.06 | 0.658 |
6B | 17.09 | 6.83-42.76 | 20.81 | 9.94-43.55 | 0.737 |
18C | 42.73 | 19.34-94.41 | 47.60 | 24.53-92.37 | 0.833 |
19A | 17.41 | 9.93-30.52 | 22.54 | 12.56-40.46 | 0.522 |
Fold increase in geometric mean titers after vaccination in the two study arms for serotypes 5, 6B, 18C, and 19A. CI, confidence interval.