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Improving the Immunogenicity of Pneumococcal Conjugate Vaccine in HIV-Infected Adults with a Toll-Like Receptor 9 Agonist Adjuvant: A Randomized, Controlled Trial

  1. Ole S. Søgaard1,
  2. Nicolai Lohse1,
  3. Zitta B. Harboe2,
  4. Rasmus Offersen1,
  5. Anne R. Bukh1,
  6. Heather L. Davis4,
  7. Henrik C. Schønheyder3, and
  8. Lars Østergaard1
  1. 1Department of Infectious Diseases, Aarhus University Hospital, Skejby
  2. 2Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen
  3. 3Department of Clinical Microbiology, Aarhus University Hospital, Aalborg, Denmark
  4. 4Pfizer Vaccines Research, Ottawa, Ontario, Canada
  1. Reprints or correspondence: Dr Ole Schmeltz Søgaard, Dept of Infectious Diseases, Aarhus University Hospital, Skejby, Brendstrupgaardvej 100, 8200 Aarhus N, Denmark (olesoega{at}rm.dk).
 
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Abstract

Background. Persons infected with human immunodeficiency virus (HIV) are often hyporesponsive to immunization, including pneumococcal vaccines. We hypothesized that adding CPG 7909, a toll-like receptor 9 (TLR9) agonist and vaccine adjuvant, to 7-valent pneumococcal conjugate vaccine (7vPnC) would increase its immunogenicity in HIV-infected adults.

Methods. We performed a double-blind, placebo-controlled, phase 1b/2a trial randomizing HIV-positive patients to receive double doses of 7vPnC (Prevnar) at 0 and 3 months and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23; Pneumo Novum) at 9 months, with experimental patients receiving 1 mg of CPG 7909 added to each of their 3 vaccine doses; control patients had phosphate-buffered saline added instead. Immunogenicity and safety were evaluated for up to 10 months. The primary end point was the proportion of vaccine high responders at 9 months, defined as a 2-fold increase in IgG levels to ⩾1 µg/mL for at least 5 of 7 of the 7vPnC serotypes.

Results. Ninety-seven participants were included in the study. The proportion of vaccine high responders was higher in the experimental group (n = 48) than among controls (n = 49; 48.8% vs 25.0%; P=.02) at 9 months. Greater proportions of high responders were also observed at 3 (51.1% vs 39.6%; P=.26), 4 (77.3% vs 56.3%; P=.03), and 10 months (87.8% vs 51.1%; P<.001). Mild systemic and injection site reactions to 7vPnC were more common in the experimental group than the control group (100% vs 81.3%; P=.002). CPG 7909 did not increase non-7vPnC IgG levels after PPV-23 immunization. No adverse effects on CD4+ cell count or organ functions occurred in either group.

Conclusions. The addition of a TLR9 agonist to 7vPnC significantly enhanced the proportion of vaccine high responders.

Trial registration. ClinicalTrials.gov identifier: NCT00562939.

Persons infected with human immunodeficiency virus (HIV), even when well controlled by highly active antiretroviral therapy (HAART), have a 6-fold higher incidence of pneumonia [1] and up to a 40-fold higher incidence of invasive pneumococcal disease compared with non—HIV-infected persons, and pneumococcal disease is a major cause of morbidity and mortality among HIV-infected individuals [2–5]. Two different types of pneumococcal vaccines are currently available. Among children and adults with HIV, 23-valent pneumococcal polysaccharide vaccine (PPV-23) elicits only modest increases in serotype-specific antibody concentrations, causes antibody titers to wane quickly, and produces functional antibody responses that are lower than in healthy controls [6–8]. Furthermore, reports on PPV-23 effectiveness in reducing rates of pneumococcal disease among HIV patients are inconsistent [4, 5, 9, 10]. The 7-valent pneumococcal conjugated vaccine (7vPnC) was developed for use in infants and has proven highly effective in reducing pneumococcal disease [11]. However, a single 7vPnC immunization has not been shown to be superior to PPV-23 immunization in HIV-infected adults [12–14]. Thus, a more immunogenic pneumococcal vaccine is needed for immunocompromised adults, and this could possibly be achieved with the addition of an adjuvant.

CPG 7909 is a synthetic oligodeoxynucleotide containing CpG motifs that activate human B cells and plasmacytoid dendritic cells via toll-like receptor 9 (TLR9), which can in turn promote antigen-specific antibody secretion [15]. Although CpG oligodeoxynucleotides significantly enhance antibody responses to pneumococcal protein-conjugate antigens in mice [16, 17], their adjuvant effect is less certain when coadministered with T-independent pneumococcal polysaccharide antigens [18]. Clinical data indicate that CPG 7909 is highly effective for enhancing antigen-specific antibody responses against a variety of antigens and is generally well tolerated in HIV-negative and HIV-infected persons [15, 19–22]. However, it had not previously been tested in humans with a conjugate or polysaccharide pneumococcal vaccine. Our objective was to evaluate whether the addition of a TLR9 agonist to 7vPnC and PPV-23 would increase immunogenicity and affect clinical safety in HIV-infected adults.

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Methods

Study design. This was an investigator-initiated, phase 1b/2a, randomized, double-blind, placebo-controlled trial randomizing persons with HIV to immunization with pneumococcal vaccines. The study protocol was approved by the DanishMedicines Agency, the Regional Ethical Committee, and the Danish Data Protection Agency. The study was monitored for regulatory compliance and data quality by the Division of Good Clinical Practice at Aarhus University Hospital.

Setting and participants. The study was conducted at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. HIV patients seen at the outpatient clinic during 2007 were invited by letter to participate. Consenting HIV-seropositive volunteers 18 years or older were eligible for enrollment.We excluded individuals who (1) had received PPV-23 immunization within the last 5 years, (2) had been receiving antiretroviral therapy for <6 months or had an HIV RNA level of >50 copies/mL, (3) had CD4+ cell counts <200 cells/µL, (4) were considered unable to follow the protocol regimen, and (5) were pregnant, breast-feeding, or unwilling to use reliable contraception methods for the duration of the trial.

Randomization and interventions. Previous studies indicated that a single dose of 7vPnC was less immunogenic than a double dose in adults [23, 24]. Thus, all participants were immunized with double the standard dose of 7vPnC (Prevnar) at 0 and 3 months and with 1 single dose of PPV-23 (Pneumo Novum) at 9 months. Participants were also seen at 4 and 10 months for immunogenicity and safety follow-up. The experimental group received 1 mg of CPG 7909 (formulated in 100 mL of phosphate-buffered saline [PBS]) added to each of their 3 vaccine doses, whereas controls received an equal volume of PBS (similar in color and viscosity to CPG 7909) added to their vaccines. CPG 7909 (Coley Pharmaceutical Group) is a 24-mer oligodeoxynucleotide (sequence 5′-TCGTCGTTTTGTCGTTTTGTCGTT- 3′) comprising 4 CpG motifs, including 3 GTCGTT motifs that were found optimal for activating human TLR9. CPG 7909 (0.5 or 1 mg), added to different antigens, had been tested in clinical studies [19–21]. CPG 7909 and PBS were prepared and delivered in identical syringes by the hospital pharmacy. Pneumococcal vaccines were drawn up and mixed with CPG 7909 or placebo immediately before immunization. Trained study nurses and physicians administered all immunizations, which were injected into the right or left arm according to the participant's preference. Before any trial procedures, blood samples were collected for immunogenicity measurements and safety laboratory tests, including HIV RNA level, CD4+ cell count, hemoglobin, erythrocyte volume fraction, white blood cell count, alkaline phosphatase, alanine aminotransferase, and creatinine parameters.

Participants were stratified according to use of HAART and randomized in blocks of 6 at a ratio of 1:1 to receive pneumococcal vaccines with or without CPG 7909. Random allocation sequences were computer generated by the hospital pharmacy. Participants were assigned their study identification number according to the chronological order in which they were enrolled. Participants and study site personnel were masked to the assigned vaccine adjuvant throughout the study.

Assessment of immunogenicity. The primary objective was to compare the vaccine-specific IgG antibody response after 7vPnC immunization with or without CPG 7909 as adjuvant. The secondary objective was to compare functional activity of vaccine-specific antibodies. Specific IgG levels for 7vPnC serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and 3 non-7vPnC serotypes (1, 7F, and 19A) were analyzed in one batch using a standardized enzyme-linked immunosorbent assay method as previously reported [25] by the Statens Serum Institut. Serum samples were preadsorbed with optimal concentrations of pneumococcal cell wall and 22F capsular polysaccharides [26]. Opsonophagocytic activity of anticapsular antibodies (serotypes 6B, 14, 19F, and 23F) was measured using a flow-cytometric opsonophagocytic (Flow Applications) assay giving indirect information on the antibodies ability to opsonize and facilitate killing of invading pneumococci [27]. Serum samples were stored at −80°C before shipment for analyses.

Assessment of safety. Participants were observed for 30 minutes after each immunization to evaluate immediate adverse events and were given diary cards to record solicited adverse events occurring during the first 4 days after each immunization (injection site pain, erythema, fever, headache, nausea, myalgia, arthralgia, and rash) and other signs of illness and/or changes in medication occurring within 15 days after immunization. Solicited and unsolicited adverse events, as well as laboratory tests, were graded according to the common toxicity criteria, version 2.0 [28]. All solicited local (injection site) and influenza-like (fever, arthralgia, chills, and fatigue) reactions were considered causally related to vaccination. Other adverse events were evaluated by the primary investigator and graded as “unlikely” or “probably” related to study product. Serious adverse events were defined according to the guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use [29].

Statistical analysis. The primary end point was the proportion of vaccine high responders at 9 months, defined as having a 2-fold increase in IgG levels to at least 1 µg/mL, for a minimum of 5 of 7 of the 7vPnC serotypes. In a 7vPnC-PPV-23 prime-boost trial, 30% of participants with HIV were vaccine high responders 20 weeks after second immunization [30]. We hypothesized that the addition of CPG 7909 to 7vPnC would double the proportion of vaccine high responders, resulting in proportions of vaccine high responders of 60% and 30% in the experimental and control groups, respectively. Setting type I error probability (α) to .05 (2-sided) and type II error probability (β) to .20 (power=1−β=.80), we found that 42 patients per group were required to detect this difference. On the basis of previous experience, a study dropout rate of 10% was anticipated, so we aimed to include ∼94 patients.

Continuous variables were summarized using medians with interquartile ranges. Dichotomous and categorical variables were summarized using numbers and percentages.We used the Pearson χ2 test to compare proportions of vaccine high responders We conducted an intention-to-treat analysis of all randomized patients on the primary end point. Because the trial was designed as an explanatory trial, we used a per protocol approach for the remaining analyses of immunogenicity and safety [31]. We performed per protocol analyses of the proportion of vaccine high responders at 3, 4, 9, and 10 months.

We calculated crude odds ratios (ORs) for the effect of CPG 7909 on the primary end point among all participants and in subgroups (current smoker [yes or no], baseline CD4+ cell count [<500 or ⩾500 cells/µL], use of HAART [yes or no], body mass index [<25 or ⩾25], sex [male or female], and age [<50 or ⩾50 years]). An adjusted estimate was obtained with a logistic regression model that included all variables.

We used the χ2 test to compare the proportion of adverse events between the experimental group and the control group. We used the 2-way t test to analyze for group differences in CD4+ cell count and log-transformed HIV RNA change from baseline and performed subanalyses of the 2 variables stratified according to HAART use. We used Stata software, version 9.2 (StataCorp), for statistical analyses.

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Results

Study population. Of the 370 individuals invited to participate, 107 signed up and were screened for eligibility, and 97 of these were subsequently enrolled in the trial between 21 January and 5 March 2008 (Figure 1). The trial ended on 16 January 2009, when the last participant was seen for follow-up. Nine participants did not complete the 3-dose vaccination series: 3 withdrew consent, 4 were lost to follow-up, 1 was inappropriately enrolled (HIV RNA level, >50 copies/mL), and 1 missed PPV-23 immunization at the fourth visit. The 2 groups were similar in immune status and baseline characteristics at the time of inclusion in the study (Table 1).

Figure 1
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Figure 1

Disposition of study participants. 7vPnC, 7-valent pneumococcal conjugate vaccine; ART, antiretroviral therapy; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; PPV-23, 23-valent pneumococcal polysaccharide vaccine.

Immunogenicity. In an intention-to-treat analysis, 21 (43.8%) of 48 and 12 (24.5%) of 49 were 7vPnC high responders at 9 months in the experimental and control groups, respectively (P=.045). In the per protocol analysis (Figure 2), more high responders were found among the experimental group compared with the control group at all time points: 24 (51.1%) of 47 versus 19 (39.6%) of 48 at 3 months (P=.26), 34 (77.3%) of 44 versus 27 (56.3%) of 48 at 4 months (P=.03), 21 (48.8%) of 43 versus 12 (25.0%) of 48 at 9 months (P=.02), and 36 (87.8%) of 41 versus 24 (51.1%) of 47 at 10 months (P<.001). The crude OR of being a vaccine high responder at 9 months was 2.86 (95% CI, 1.18-6.94) in the experimental versus control group and 3.32 (95% CI, 1.22-9.02) after adjustment for current smoking status, baseline CD4+ cell count, use of HAART, AIDS, body mass index, sex, and age (Figure 3).

Figure 2
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Figure 2

The proportion of pneumococcal vaccine high responders among those receiving CPG 7909 compared with placebo adjuvant. Vaccine high responders are defined as those with a 2-fold increase in IgG levels to ⩾1 µg/mL for at least 5 of 7 serotypes in the 7vPnC. Arrows indicate the time of immunization. 7vPnC, 7-valent pneumococcal conjugate vaccine; PPV-23, 23-valent pneumococcal polysaccharide vaccine. *P<.05; ** P P<.001.

Figure 3
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Figure 3

The effect of CPG 7909 versus placebo adjuvant on the primary end point among subgroups and in total (unadjusted and adjusted). BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CI, confidence interval; OR, odds ratio. *Adjusted for current smoker (yes vs no), baseline CD4+ cell count (<500 vs ⩾500 cells/µL), use of HAART (yes vs. no), BMI (<25 vs ⩾25), sex (male vs female), and age (<50 vs ⩾50 years).

At baseline, IgG concentrations were lower for all 7vPnC serotypes in the experimental group compared with the control group, although it was only statistically significant for serotype 19F (Table 2). After PPV-23 immunization, both the experimental group and control group experienced 2–5-fold increases in geometric mean concentrations for non-7vPnC serotypes, but there were no significant group differences in geometric mean ratios. After the second 7vPnC and PPV-23 immunizations, opsonophagocytic activity geometric mean ratios were between 1.10 and 1.62 for the 4 serotypes when comparing the experimental with the control group (Table 2).

Table 1
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Table 1

Baseline Characteristics of the Study Population at Time of Inclusion in the Study

Table 2
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Table 2

Geometric Mean (GM) Concentrations of Immunoglobulin (Ig) G Antibodies and GM of Opsonophacytic Activity (OPA) Titers of Persons with Human Immunodeficiency Virus Receiving Pneumococcal Vaccines with or without CPG 7909

Safety. The 7vPnC with or without CPG 7909 was generally well tolerated (Table 3), but mild systemic and injection site reactions to first and/or second 7vPnC were more common in the experimental group compared with the control group (100% vs. 81.3%; P=.002). Three individuals, all from the experimental group, withdrew their consent after the first 7vPnC immunization. All 3 stated injection site reactions as a contributory cause to their withdrawal. No serious adverse events were seen in either group in relation to the first 2 immunizations.

Table 3
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Table 3

Injection-Related Adverse Events

After PPV-23 immunization, 37 (90.2%) of 41 participants in the experimental group experienced influenza-like symptoms compared with 2 (4.3%) of 47 in the control group (P<.001). In the experimental group, 31 (75.6%) of 37 were graded as moderate to severe in intensity (common toxicity criteria grade 2–3). One of the last individuals to receive PPV-23 was admitted to the department with fever and malaise 2 days after immunization (plus CPG 7909). He received intravenous antibiotics and underwent extensive laboratory testing; however, no infectious focus was identified. The patient was discharged 5 days later and had fully recovered at follow-up 3 weeks later (normal biochemical analysis results and no abnormal signs or symptoms). Although prevaccination geometric mean concentrations for the 7vPnC serotypes were 17%–77% higher among those experiencing influenza-like symptoms compared with those without such symptoms, many controls with high 7vPnC antibody concentrations had no systemic reactions to PPV-23.

We found no adverse effect of CPG 7909 on CD4+ cell counts in total or when stratified according to use of HAART and no difference in HIV RNA at any time points between the 2 groups (data not shown). In the control group, HAART-naive patients had a significant decrease in HIV RNA from baseline to 3 months (−0.27 log10 HIV RNA; P=.005), whereas HAART-naive patients in the experimental group had a significant increase at 10 months (+0.29 log10 HIV RNA; P=.02). Five (50%) of 10 HAART-naive individuals in the control group and none (0 of 10) in the experimental group had been diagnosed as having HIV infection <15 months before study inclusion. One HAART-naive individual at baseline in each group initiated HAART between months 4 and 9. None of those receiving HAART, in either group, experienced persistent viremia (⩾2 consecutive HIV RNA measurements of 150 copies/mL) during the trial. We did not observe changes in liver, kidney, or hematologic parameters in either group during the trial.

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Discussion

In this trial, we found that the addition of CPG 7909, a TLR9 agonist, to 7vPnC increased the proportion of patients achieving a high vaccine-specific IgG antibody response at 9 months. The TLR9 agonist adjuvant also induced a more durable antibody response of higher magnitude than when 7vPnC was administered alone. Subsequent boosting with PPV-23 resulted in increased production of antibodies with higher functional activity in the experimental group compared with the control group. Mild systemic and injection site reactions to 7vPnC were more common in the experimental group, but the overall safety of the TLR9 adjuvant 7vPnC was acceptable for both patients and physicians. The addition of CPG 7909 to PPV-23 is not desirable because it did not enhance the antibody response to non-7vPnC serotypes and increased the incidence of moderate to severe influenza-like reactions.

One of the strengths of the study was that all participants and trial site and laboratory personnel were masked to the assigned test drug throughout the trial, leading to unbiased safety and immunogenicity measurements. The study was adequately powered to detect a 2-fold difference in the proportion of vaccine high responders between the 2 groups, and it is unlikely that the observed differences were due to chance. Furthermore, the randomization was considered successful because the 2 groups were comparable in size and baseline characteristics. The study was conducted at a single trial site, minimizing variations in trial procedures and blood sample analyses.

The study also had several limitations. Because this was the first human trial of TLR9 agonist adjuvant pneumococcal vaccination, we do not have information on the antibody response in an HIV-negative control group. We did not measure immunogenicity after the first and second 7vPnC immunizations at the same time points; therefore, we could not assess the effect of administering a second 7vPnC compared with just one. This was a proof-of-concept study and not designed to find the optimal dosing of vaccine or adjuvant. Adjustments in either component, as well as dosing schedule, could lead to improved immunogenicity and/or reduced adverse reactions [15, 32, 33]. Baseline 7vPnC specific IgG concentrations were lower in the experimental group compared with the control group, which may have increased the controls' chance of reaching high post vaccination IgG levels. If so, this would cause us to underestimate the effect of CPG 7909. The primary end point was based on serologic test results, and the trial was not powered to detect differences in clinical end points (ie, all-cause pneumonia or invasive pneumococcal disease). However, high postimmunization antibody levels correlate with a reduced risk of vaccine-specific pneumococcal disease [34, 35]. We did not have long-term follow-up and cannot predict decreases in antibody response over time. Cooper et al. [19] found that the addition of CPG 7909 to a commercial hepatitis B virus vaccine resulted in high hepatitis B virus seroprotection in HIV-infected adults, which was sustained even at 5 years of follow-up [36]. Finally, we used double doses of 7vPnC, most participants were following a HAART regimen, and CD4+ cell counts were high (median >600 cells/µL in both groups), which may have increased the antibody responses above the levels observed in other pneumococcal vaccination trials in people with HIV [30].

In our study, CPG 7909 was safe to use with 7vPnC but increased the risk of mild injection site and influenza-like reactions consistent with other clinical studies adding CPG 7909 to commercial or experimental vaccines [19, 21, 22]. Our use of double doses of 7vPnC may have increased adverse reactions among both controls and those receiving CPG 7909 [37]. The lack of effect of CPG 7909 on PPV-23 immunogenicity was not unexpected because these are T-independent antigens previously shown in animals not to respond to the adjuvant effect of CpG oligodeoxynucleotides [18]. Furthermore, the safety profile of CPG 7909 and PPV-23 was not optimal. The systemic reactions induced by this combination were uncommon among those who received PPV-23 alone, even when they had high prevaccination pneumococcal antibody concentrations. Thus, the influenza-like reactions were unlikely caused by preexisting antibodies and more likely by the immunostimulatory effects of CPG 7909 combined with PPV-23. Surprisingly, we found that HAART-naive controls experienced a decrease in HIV RNA levels after the second 7vPnC immunization. One-half of these patients were diagnosed as having HIV within 6–15 months of study inclusion but should have reached their viral set point by the beginning of the study. We regard the result as a chance finding. After PPV-23 vaccination, HAART-naive patients in the experimental group had a small increase in HIV RNA level, which may have been a result of the general immune activation induced by PPV-23 and CPG 7909. In accordance with other studies, we found no adverse effects from CPG 7909 on CD4+ cell count [19] or biochemical markers of organ functions [15].

In conclusion, we have shown the immunogenicity of a TLR9 agonist adjuvant pneumococcal conjugate vaccine is superior to that of the vaccine alone in patients with well-controlled HIV. The safety profile of the combination of vaccine and adjuvant is acceptable. In time, pneumococcal conjugate vaccines may completely replace PPV-23 for adult vaccination. In populations that are hyporesponsive to immunization, adding TLR9 agonists as adjuvants could be the key to improving the immunogenicity of multivalent pneumococcal conjugate vaccines.

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Acknowledgments

We thank the participants for their involvement in the trial. We also thank the study nurses, Iben Loftheim and Inge Arbs, for their excellent work as trial site coordinators for the study; Arthur M. Krieg for his comments on the manuscript; Coley Pharmaceutical Group (now part of Pfizer) for providing CPG 7909 for the study; and Statens Serum Institut and Flow Applications Inc for conducting the antibody analyses.

Financial support. Grant support was provided by Aarhus University, the Augustinus Foundation, Scandinavian Society for Antimicrobial Chemotherapy, Danielsen's Foundation, AP Moeller's Foundation, Krista and Viggo Pedersen's Foundation, L. F. Foght's Foundation, K. A. Rohde, and Hustru's Foundation.

Potential conflicts of interest. H.L.D. is a former employee of Coley Pharmaceutical Group and a current employee of Pfizer Vaccines Research. All other authors: no conflicts.

  • Received October 29, 2009.
  • Accepted March 12, 2010.
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  1. Clin Infect Dis. (2010) 51 (1): 42-50. doi: 10.1086/653112
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