ABSTRACT
HIV-infected patients are 30- to 100-fold more susceptible to invasive pneumococcal diseases than are healthy adults. Pneumococcal vaccination may be the best way to decrease the large pneumococcal disease burden, but the optimal timing of vaccination is still unclear. In this study, HIV-infected subjects aged ≥18 years were recruited and divided into 2 age-matched groups: group 1 (subjects with CD4 T-cell count ≥350 cells/µL) and group 2 (CD4 T-cell count <350 cells/µL). Multiplex opsonophagocytic killing assay was used to compare immunogenicity after immunization with 13-valent pneumococcal conjugate vaccine (PCV13). Among 70 subjects, 67 (group 1, N = 34; group 2, N = 33) were available for the assessment of immunogenicity and safety. With respect to the post-vaccination geometric mean titer (GMT) ratios, the non-inferiority criteria were not met. Post-vaccination GMTs were significantly lower in group 2 compared to group 1 for all 4 pneumococcal serotypes (5, 6B, 18C, and 19A) tested. PCV13 was safe and well tolerated in HIV-infected patients irrespective of immune status. In conclusion, PCV13 showed significantly inferior immunogenicity among HIV-infected patients with CD4 T-cell count <350 cells/µL compared to those with a higher CD4 T-cell count.
KEYWORDS: Pneumococcal conjugate vaccine, HIV, vaccination, immunogenicity
Introduction
Chronically ill patients have a 2- to 8-fold higher risk of developing invasive pneumococcal disease (IPD) compared with healthy adults.1 In particular, HIV-infected patients are reportedly 30- to 100-fold more susceptible to IPD.2,3 Moreover, HIV-infected patients are known to have a 6-fold higher risk of recurrent pneumococcal infection within a year.4 Since the introduction of highly active antiretroviral therapy (HAART) in the late 1990s, the average life span of HIV-infected people has increased significantly; older age and its concomitant comorbidities have likely caused the reported increased case fatality rate of IPD in this population.5
In HIV-infected patients, several aspects explain the large pneumococcal disease burden. First, the pneumococcal colonization rate and density are significantly high in the nasopharyngeal mucosa of HIV-infected patients.6 It was shown that the nasopharyngeal pneumococcal carriage rate increased markedly in symptomatic HIV-infected patients, and even after CD4 T-cell count recovery with HAART, the high pneumococcal carriage was maintained.6 Dysfunction of Th1 and Th17 cells in HIV-infected individuals is related to the high pneumococcal carriage rate.7,8 Normally, Th1 and Th17 cells secrete IFN-γ and TGF-β, respectively, to stimulate the isotype switching of B cells and IgA secretion, respectively, thereby inhibiting bacterial colonization.9,10 In addition, Th17 cells recruit inflammatory cells such as neutrophils and monocytes, and secrete antimicrobial peptides, including β-defensin, to inhibit bacterial colonization.7
Another reason for the vulnerability of HIV-infected individuals to pneumococcal infection is loss of regulatory T-cells and persistent inflammation due to chronic viral infection; the function of available immune cells deteriorates, resulting in the development of severe infection.8,11 Despite initiation of HAART, the inflammation cycle continues to progress, and T-cell and B-cell function does not fully recover, even after 1–2 years of therapy.11
Current guidelines recommend that all HIV-infected individuals should receive 13-valent pneumococcal conjugate vaccine (PCV13) immunization irrespective of CD4 T-cell count.12,13 After the CD4 T-cell count has recovered to over 200 cells/µL, the 23-valent pneumococcal polysaccharide vaccine (PPV23) should be additionally administered.12,13 PCV13 and PPV23 should be given sequentially at least 8 weeks apart. However, the optimal time to administer the initial PCV13 is still unclear with respect to CD4 T-cell count. In this study, we aimed to compare the immunogenicity of PCV13 in HIV-infected patients who received HAART for ≥4 weeks, stratified by CD4 T-cell count (≥350 cells/µL versus <350 cells/µL).
Methods
Study design
This single-center, open-label non-randomized clinical trial was conducted (Clinical Trial Number – NCT03838497) at Korea University Guro Hospital from April 2015 to January 2017. Based on the CD4 T-cell count at the time of enrollment, HIV-infected subjects aged ≥18 years were divided into 2 groups: group 1 comprising subjects with CD4 T-cell count ≥350 cells/µL and group 2 comprising subjects with CD4 T-cell count <350 cells/µL. CD4 T-cell count <350 cells/µL was the threshold for starting antiretroviral therapy in the past with limited therapeutic options.14
The primary objective of the study was to demonstrate that the immune response to PCV13 serotypes in group 2 was not inferior to that in group 1 at 1 month after vaccination. The secondary objective was comparison of the PCV13 safety profile between the 2 study groups.
HIV-infected subjects aged ≥18 years with stable underlying diseases (≥4 weeks on HAART) were eligible for inclusion in the study. All available subjects with low CD4 T-cell counts (<350 cells/µL, group 2) were recruited, and age/visit day-matched controls with high CD4 T-cell counts (≥350 cells/µL, group 1) were enrolled. The exclusion criteria were as follows: 1) a history of pneumococcal infection within the previous 5 years, 2) previous pneumococcal vaccination, 3) current opportunistic infection, 4) known immunodeficiency other than HIV infection, and 5) coagulation disorders.
The study was approved by the ethics committee of Korea University Guro Hospital (IRB No. 2014GR0014), and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from all participants before enrollment. Venous blood samples of 10 mL were collected for analysis on day 0 and post-vaccination day 28 ± 7.
Vaccines
The PCV13 (Prevnar-13®) vaccine contains polysaccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F, which are individually conjugated to nontoxic diphtheria toxin cross-reactive material 197 (CRM197). The vaccine is formulated at pH 5.8 with 5 mM succinate buffer, 0.85% sodium chloride, and 0.02% polysorbate 80, and is formulated to contain 2.2 µg of each saccharide except 6B (4.4 µg) per 0.5 mL dose. The vaccine also contains 0.125 mg aluminum as aluminum phosphate per 0.5 mL dose. A single dose of PCV13 (0.5 mL) was administered intramuscularly into the deltoid muscle of each participant.
Immunogenicity assessment
As for the immunogenicity of PCV13, the opsonophagocytic activity (OPA) of the samples was assessed using the validated multiplex opsonophagocytic killing assay as previously described.15 Target strains STREP5, SPEC6B, OREP18C, and TREP19A (expressing capsule types 5, 6B, 18C and 19A, respectively) were derived from wild-type strains DBL5, BG25-9, GP116, and DS3519-97, respectively, and have been described previously.15 Each of them was resistant to only 1 of 4 antibiotics (streptomycin, spectinomycin, optochin and trimethoprim). The OPA titer was defined as the serum dilution that killed 50% of the bacteria, and was determined by linear interpolation. A detailed protocol is posted online at http://www.vaccine.uab.edu. All laboratory personnel remained blinded throughout the entire study period. The immunogenicity between the 2 study groups was compared using the following 4 parameters: (1) percentage of patients with post-vaccination OPA titers ≥1:64 (seroprotection rate); (2) percentage of patients with ≥4-fold increase of post-vaccination OPA titers (seroconversion rate); (3) geometric mean and fold increase of post-vaccination OPA titers; and (4) geometric mean titer (GMT) ratio (group 2/group 1) of post-vaccination OPA at 1 month post-vaccination.
Safety assessment
After vaccination, solicited local and systemic reactions were monitored using diary cards during the 21 days post-vaccination. Each subject was asked to record local reactions (pain, tenderness, erythema, and induration) at the injection site and systemic symptoms (fever, headache, fatigue, chills, myalgia, and arthralgia). Any serious adverse events were monitored during the 28 days after vaccination.
Statistical analysis
Assuming the differences of seroconversion rates (90% vs. 60%) and post-vaccination OPA GMTs (300 vs. 150; 1,000 vs. 600; 9,000 vs. 3,000) between group1 and group 2, it was projected that 31 subjects per group would provide at least 80% power to declare a non-inferior immune response in Group 2 (CD4 T-cell counts <350 cells/µL) compared to Group 1 (CD4 T-cell counts ≥350 cells/µL). Considering a dropout rate of approximately 10% in each group, an enrollment of 70 subjects (35 subjects per group) was planned.
All statistical analyses were performed using SPSS 18.0 software. Descriptive statistics were reported as numbers and percentages of participants. OPA titers were expressed as geometric means with 95% confidence intervals (CIs). The Student’s t-test was used to assess the variation of GMT ratios between the 2 groups at each time point, and the Chi-square test (Fisher’s exact test if sample size <30) was conducted to compare categorical variables. Statistical significance was defined as p < .05.
For GMT ratios, CIs were computed using the Student’s t-test for the mean difference of the measures on the log scale. Non-inferiority was defined as the lower limit of the two-sided 95% CI for the GMT ratio (group 2/group 1) at 1 month post-vaccination being >0.5 (2-fold criterion). Results were considered significantly lower if the upper limit of the 95% CI for the GMT ratio was <1.0.
Results
Baseline characteristics
A total of 70 subjects were initially recruited, with 35 in each group. Of these 70, 67 (group 1, N = 34; group 2, N = 33) completed the study through the 1 month follow-up period after the vaccination, and were included in the assessment of immunogenicity and safety (Figure 1). Except for immune status, baseline demographics were indistinguishable between the study groups (Table 1). Most subjects received HAART with an integrase inhibitor-based regimen (83.6%, 56 of 67 cases), followed by protease inhibitor-based (10.4%), and non-nucleoside reverse transcriptase inhibitor-based (6.0%) regimens.
Figure 1.
Study flow chart.
Table 1.
Baseline characteristics of study subjects.
| Characteristics | Group 1 (N = 34) | Group 2 (N = 33) | p-value |
|---|---|---|---|
| Mean age in years (95% CI) | 40.9 (36.5–45.2) | 42.3 (38.4–46.1) | 0.623 |
| Age groups, No. (%) | 0.853 | ||
| 18–29 years | 7 (20.6) | 5 (15.2) | |
| 30–49 years | 21 (61.8) | 22 (66.7) | |
| 50–64 years | 4 (11.8) | 5 (15.2) | |
| ≥ 65 years | 2 (5.9) | 1 (3.0) | |
| Male, No. (%) | 32 (94.1) | 30 (90.9) | 0.617 |
| Body mass index, mean ± SD (kg/m2) | 22.0 ± 2.7 | 22.1 ± 4.1 | 0.921 |
| CD4 T-cell count, cells/µL (95% CI) | 579 (519–640) | 200 (167–234) | <0.001 |
| Immune status groups, No. (%) | <0.001 | ||
| CD4 T-cell count ≥500 cells/µL | 20 (58.8) | 0 (0) | |
| CD4 T-cell count 350–499 cells/µL | 14 (41.2) | 0 (0) | |
| CD4 T-cell count 200–349 cells/µL | 0 (0) | 17 (51.5) | |
| CD4 T-cell count <200 cells/µL | 0 (0) | 16 (48.5) | |
| Plasma HIV RNA viral load, copies/mL | 6,757 (898–12,616) | 13,556 (3,304–23,807) | 0.242 |
| Undetectable plasma HIV RNA, No. (%) | 21 (61.8) | 17 (51.5) | 0.464 |
| Antiretroviral regimen | 0.146 | ||
| Integrase inhibitor-based | 26 (76.5) | 30 (90.9) | |
| Protease inhibitor-based | 6 (17.6) | 1 (3.0) | |
| NNRTI-based regimen | 2 (5.9) | 2 (6.1) | |
| Diabetes, No. (%) | 1 (2.9) | 3 (9.1) | 0.288 |
| Chronic renal diseases, No. (%) | 0 (0) | 2 (6.1) | 0.145 |
| Chronic heart diseases, No. (%) | 1 (2.9) | 1 (3.0) | 0.983 |
| Chronic liver diseases, No. (%) | 2 (5.9) | 1 (3.0) | 0.573 |
CI, confidence interval; NNRTI, non-nucleoside reverse transcriptase inhibitor.
Group 1: HIV-infected subjects with CD4 T-cell counts ≥350 cells/µL.
Group 2: HIV-infected subjects with CD4 T-cell counts <350 cells/µL.
Immunogenicity to PCV13
The baseline OPA GMTs of all 4 serotypes (5, 6B, 18C, and 19A) were indistinguishable between group 1 and group 2 (Table 2). Although OPA titers increased markedly after the PCV13 vaccination irrespective of baseline CD4 T-cell count, post-vaccination OPA GMTs were significantly higher in group 1 (CD4 T-cell counts ≥350 cells/µL) compared to group 2 (CD4 T-cell counts <350 cells/µL) (Table 2, 3 and Figure 2(a)).
Table 2.
Comparison of geometric mean titers for opsonophagocytic activity (OPA) after administration of 13-valent pneumococcal conjugate vaccine (PCV13): analysis stratified by CD4 T-cell count.
| Serotype | Group | Pre-vaccination OPA |
p-value | Post-vaccination OPA |
p-value | ||
|---|---|---|---|---|---|---|---|
| GMT | 95% CI | GMT | 95% CI | ||||
| 5 | 1 | 4 | 3–6 | 0.286 | 304 | 169–547 | 0.001 |
| 2 | 3 | 2–4 | 57 | 26–128 | |||
| 6B | 1 | 96 | 31–302 | 0.878 | 9594 | 7211–12764 | <0.001 |
| 2 | 86 | 29–256 | 1750 | 731–4197 | |||
| 18C | 1 | 26 | 16–41 | 0.684 | 297 | 210–421 | 0.007 |
| 2 | 23 | 13–39 | 135 | 85–215 | |||
| 19A | 1 | 227 | 99–521 | 0.139 | 9397 | 7015–12589 | <0.001 |
| 2 | 97 | 43–217 | 1726 | 935–3191 | |||
OPA, opsonophagocytic activity; CI, confidence interval; GMT, geometric mean titer.
Group 1: HIV-infected subjects with CD4 T-cell count ≥350 cells/µL.
Group 2: HIV-infected subjects with CD4 T-cell count <350 cells/µL.
Table 3.
Comparison of immune responses after administration of 13-valent pneumococcal conjugate vaccine (PCV13).
| Serotype | Parameters of immunogenicity | Group 1 (N = 34) | Group 2 (N = 33) | p-value |
|---|---|---|---|---|
| 5 | Seroprotection rate (%) | 27 (79.4) | 17 (51.5) | 0.021 |
| Seroconversion rate (%) | 31 (91.2) | 25 (75.8) | 0.109 | |
| GMT fold increase (95% CI) | 72.9 (35.8– 148.3) | 18.3 (7.7–43.5) | 0.053 | |
| 6B | Seroprotection rate (%) | 34 (100) | 29 (87.9) | 0.053 |
| Seroconversion rate (%) | 25 (73.5) | 20 (60.6) | 0.305 | |
| GMT fold increase (95% CI) | 99.5 (30.8–321.7) | 20.5 (5.2–80.9) | 0.088 | |
| 18C | Seroprotection rate (%) | 32 (94.1) | 25 (75.8) | 0.045 |
| Seroconversion rate (%) | 26 (76.5) | 20 (60.6) | 0.194 | |
| GMT fold increase (95% CI) | 11.3 (6.5–19.9) | 5.9 (3.0–11.8) | 0.650 | |
| 19A | Seroprotection rate (%) | 34 (100) | 31 (93.9) | 0.239 |
| Seroconversion rate (%) | 29 (85.3) | 25 (75.8) | 0.369 | |
| GMT fold increase (95% CI) | 41.3 (17.2–98.8) | 17.8 (6.6–48.0) | 0.956 |
CI, confidence interval; GMT, geometric mean titer.
Group 1: HIV-infected subjects with CD4 T-cell counts ≥350 cells/µL.
Group 2: HIV-infected subjects with CD4 T-cell counts <350 cells/µL.
Figure 2.
(a) Spider web plots of opsonophagocytic activity (OPA) geometric mean titer (GMT) ratio comparisons for group 1 and group 2 following vaccination. Black dotted line: pre-vaccination, group 1; gray dotted line: pre-vaccination, group 2; black solid line: post-vaccination, group 1; gray solid line: post-vaccination, group 2. Significant differences were observed for all 4 serotypes between group 1 and group 2 (p < .01). (b) OPA GMT ratios at 1 month post-vaccination: group 2 (CD4 T-cell count <350 cells/µL, N = 33) versus group 1 (CD4 T-cell count ≥350 cells/µL, N = 34). Non-inferiority was defined as the lower limit of the two-sided 95% CI for the GMT ratio (group 2/group 1) at 1 month post-vaccination being >0.5 (2-fold criterion). The immune response of group 2 was considered significantly lower compared with group 1 if the upper limit of the 95% CI for the GMT ratio was <1.0.
When comparing the proportion of patients with OPA titers >1:64, seroprotection rates were significantly higher in group 1 than group 2, particularly for serotype 5 (79.4% versus 51.5%, respectively; p = .021) and 18C (94.1% versus 75.8%, respectively; p = .045) (Table 3). Seroconversion rates were also higher in group 1 (range 73.5%–91.2%) versus group 2 (range 60.6%–75.8%), but the difference was not statistically significant.
With respect to the post-vaccination GMT ratios, the non-inferiority criteria were not met for all 4 tested pneumococcal serotypes (Figure 2(b)). After the administration of PCV13, the immune response was significantly lower in group 2 compared to group 1; the upper limit of the 95% CI for the GMT ratio (group 2/group 1) was lower than 1.0 for all 4 pneumococcal serotypes (Figure 2(b)).
Safety
Table 4 shows the local and systemic adverse events that occurred within 14 days after vaccination. There was no significant difference in local (pain, tenderness, erythema and induration) and systemic (fever, headache, chill, myalgia, and arthralgia) reactions between the 2 study groups. The most common local reactions were pain (31.3%, 21 of 67 subjects) and tenderness (35.8%, 24 of 67 subjects) at the injection site. As for the systemic adverse events, fatigue (13.4%, 9 of 67 subjects) and myalgia (17.9%, 12 of 67 subjects) were reported most frequently. No serious vaccine-related adverse event was reported.
Table 4.
Local and systemic adverse events within 21 days after vaccination.
| Adverse events, No. (%) | Group 1 (N = 34) | Group 2 (N = 33) | p-value |
|---|---|---|---|
| Local reactions | |||
| Pain | 8 (23.5) | 13 (39.4) | 0.194 |
| Tenderness | 10 (29.4) | 14 (42.4) | 0.314 |
| Redness diameter | 0.592 | ||
| 0 mm | 32 (94.1) | 31 (93.9) | |
| 1–9 mm | 2 (5.9) | 1 (3.0) | |
| ≥10 mm | 0 (0) | 1 (3.0) | |
| Swelling diameter | 0.592 | ||
| 0 mm | 33 (97.1) | 31 (93.9) | |
| 1–9 mm | 1 (2.9) | 1 (3.0) | |
| ≥10 mm | 0 (0) | 1 (3.0) | |
| Systemic reactions | |||
| Fever, temp (≥38℃) | 0 (0) | 0 (0) | - |
| Headache | 1 (2.9) | 3 (9.1) | 0.288 |
| Fatigue | 4 (11.8) | 5 (15.2) | 0.684 |
| Chills | 1 (2.9) | 1 (3.0) | 0.983 |
| Myalgia | 5 (14.7) | 7 (21.2) | 0.539 |
| Arthralgia | 1 (2.9) | 2 (6.1) | 0.537 |
Group 1: HIV-infected subjects with CD4 T-cell counts ≥350 cells/µL.
Group 2: HIV-infected subjects with CD4 T-cell counts <350 cells/µL.
Discussion
In this study, we found that the immunogenicity of PCV13 was significantly inferior among HIV-infected patients with CD4 T-cell count <350 cells/µL compared to those with higher CD4 T-cell counts. Current guidelines recommend that HIV-infected patients should receive PCV13 vaccination irrespective of CD4 T-cell count,12,13 but it would be necessary to assess the optimal timing of vaccination to obtain sufficiently protective immunity. It is also unknown whether PCV13 revaccination is required in HIV-infected patients who received vaccination while their CD4 T-cell count was low (<200–350 cells/µL).
In a previous study, patients with a CD4 T-cell count <200 cells/µL had a significantly lower functional antibody level (OPA titer) compared to those with CD4 T-cell count ≥200 cells/µL when PPV23 was given, and the poor immune response did not improve 6 months after initiating HAART.16 Accordingly, almost all pneumococcal vaccine clinical trials have been conducted in HIV-infected individuals with a CD4 T-cell count >200 cells/µL. However, OPA titers after vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) were significantly lower even in HIV-infected patients with a moderate CD4 T-cell count (200–500 cells/µL) compared to HIV-negative subjects.17 When PCV13 was re-administered at 6-month intervals for HIV-infected patients with CD4 T-cell count ≥200 cells/µL, the OPA titer was restored to the primary post-vaccination level, but it declined again to the pre-vaccination level within 6 months.18 The effect of revaccination in patients with a CD4 T-cell count ≥200 cells/µL appears to be very limited. Thus, considering the improved immune status of HIV-infected people in the era of HAART, and inadequate acquisition of immunity after PCV13 administration to patients with a low CD4 T-cell count (even at ≥200 cells/µL), the immunogenicity of the pneumococcal vaccines needs to be reassessed using CD4 T-cell count range stratification standards.
Studies evaluating the efficacy of pneumococcal vaccines for the prevention of IPD in HIV-infected patients are very limited. In an earlier study, 1392 HIV-infected patients were randomly assigned to receive either PPV23 or placebo, and PPV23 did not show any protective effect against IPD for 3 years.19 In the first 6 months after vaccination, IPD incidence was rather higher in the PPV23 vaccination group, contrary to expectation. On the other hand, the PCV efficacy trial showed good results: 496 HIV-infected patients in Malawi were randomly assigned to PCV7 and placebo groups and followed for 3 years after vaccination; >80% of IPDs occurred in severely immunocompromised patients (CD4 T-cell count <200 cells/µL), and the PCV7 group showed significant 74% protection against IPD.20 Determining the optimal immunization timing and type of pneumococcal vaccine based on immune status would be important to achieve adequate protection against severe pneumococcal infections in HIV-infected patients.
As for the safety profile, PCV13 was safe and well tolerated in HIV-infected patients in this study irrespective of immune status. As previously reported, local pain and tenderness were the most frequent adverse events, but the incidences of local and systemic reactions were lower compared to previous reports in healthy adults.21–23
There were some limitations in this study. First, this study was conducted without healthy age-matched controls. However, indirect comparisons would be possible using data previously reported from healthy adults. Second, the immunogenicity was compared for a restricted number of pneumococcal antigens (4 of 13 serotypes). Finally, the difference in long-term immunogenicity according to CD4 T-cell count was not evaluated and further studies would be required in the future.
In conclusion, PCV13 showed significantly inferior immunogenicity when administered to HIV-infected patients with a CD4 T-cell count <350 cells/µL compared to those with better immune status (CD4 T-cell count ≥350 cells/µL).
Funding Statement
This work was supported by a Korea University Guro Hospital grant (no. I1404281) that was underwritten by AbbVie Inc;AbbVie Inc.
Disclosure of potential conflicts of interest
No potential conflict of interest was reported by the authors.
Author contributions
JYS and HJC conceived and designed the experiments. All authors participated in the enrollment of study subjects and data collection. JYS, JYN and MJC analyzed the data. JYS and HJC wrote the first draft of the manuscript. All authors reviewed the initial draft and revised the final version of the paper. All named authors meet the ICMJE criteria for authorship for this manuscript, agree with the manuscript results and conclusions, and read and approved the final manuscript.
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