Pneumococcal conjugate vaccination in persons with HIV: the effect of highly active antiretroviral therapy
Søgaard, Ole Sa; Schønheyder, Henrik Cb; Bukh, Anne Ra; Harboe, Zitta Bc; Rasmussen, Thomas Aa; Østergaard, Larsa; Lohse, Nicolaia
aDepartment of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
bDepartment of Clinical Microbiology, Aarhus University Hospital, Aalborg, Denmark
cDepartment of Bacteriology, Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark.
Received 30 December, 2009
Revised 12 March, 2010
Accepted 16 March, 2010
Correspondence to Ole S. Søgaard, MD, Department of Infectious Diseases, Aarhus University Hospital, Skejby Brendstrupgaardvej 100, 8200 Aarhus N, Denmark. Tel: +45 8949 8492; fax: +45 8949 8490; e-mail: firstname.lastname@example.org
Objective: Vaccination responses may be affected by concomitant use of highly active antiretroviral therapy (HAART). We aimed to determine HAART's impact on seven-valent pneumococcal conjugate (7vPnC) vaccine immunization with or without a Toll-like receptor 9 (TLR9) agonist adjuvant.
Design: Observational cohort study.
Methods: Adults with HIV were immunized with double doses of 7vPnC ±1 mg CPG 7909, a TLR9 agonist and vaccine adjuvant, at 0 and 3 months, and 23-valent pneumococcal polysaccharide vaccine at 9 months. We measured IgG levels (ELISA) and opsonophagocytic activity (OPA) at months 0, 3, 4, 9, and 10. Persistent 7vPnC vaccine responders were defined as individuals with two-fold IgG increases to 1 μg/ml or more for at least five of the 7vPnC serotypes at 9 months.
Results: We included 75 participants on HAART and 20 HAART-naive. Forty-one received CPG 7909 and 48 received placebo adjuvant. More persistent 7vPnC vaccine responders were found among HAART-treated than among HAART-naive (42.3 vs. 15.0%, P = 0.03). Mean loss of vaccine-specific IgG from month 4 to 9 was greater among HAART-naive than among HAART-treated (54.8 vs. 38.1%, P = 0.001). Functional activity (OPA) was higher among HAART-treated than among HAART-naive at 4, 9, and 10 months. In a logistic regression analysis (adjusted for baseline CD4+ cell count, CPG 7909, smoking status, BMI, AIDS diagnosis, and age), HAART use was significantly associated with being persistent 7vPnC vaccine responder at month 9 [odds ratio = 4.65, 95% confidence interval (CI) 1.07–20.2].
Conclusions: HIV-infected adults on HAART achieved a more durable antibody response of higher functional activity following pneumococcal conjugate vaccination than HAART-naive individuals, independently of baseline CD4+ cell count.
Persons infected with human immunodeficiency virus (HIV) have a six-fold to eight-fold higher risk of pneumonia [1,2] and up to a 40-fold higher risk of invasive pneumococcal disease compared with persons without HIV [3–6]. Immunization with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended in most HIV management guidelines , but reports on pneumococcal vaccine effectiveness in reducing rates of pneumococcal disease among HIV patients are inconsistent [5,6,8,9]. CD4+ cell count, HIV viral load, and treatment at the time of immunization may be key determinants of the clinical effectiveness of PPV23 [10,11]. Although the clinical benefit of PPV23 among HAART-naive appears limited , antibody responses to pneumococcal conjugate vaccines may be partially intact in both HAART-treated and untreated individuals [12,13].
HIV is associated with disturbance of all major lymphocyte populations, including B cells and CD4+ T cells, as well as increased lymphocyte turnover rates [14,15]. Highly active antiretroviral therapy (HAART) dramatically reduces viral replication and partially restores immune functions. In parallel with the increase in CD4+ T-cell count, HAART initiation leads to a significant increase in B-cell numbers and normalization of B-cell subpopulations [15,16]. Further, the B-cell superantigen HIV gp120 may bind to VH3, the predominant human immunoglobulin gene family used in the expression of antibodies to pneumococcal polysaccharides , and affect the qualitative antibody response in people with HIV . Thus, use of HAART may improve B-cell responses to both T-cell-independent and T-cell-dependent antigens after immunization.
CPG 7909 is a Toll-like receptor 9 (TLR9) agonist and novel vaccine adjuvant. TLR9 detects unmethylated CpG dinucleotides, which are relatively common in the genomes of most bacteria (including pneumococci ) and DNA viruses  but are suppressed and usually methylated in vertebrate genomic DNA. TLR9 expression and signaling may be perturbed by HIV viremia and chronic immune activation [21,22]. Until now, the effect of direct TLR9 stimulation on adaptive immune responses has not been studied in viremic HIV patients, but an association between viral load and responsiveness to TLR9 agonist-adjuvanted hepatitis B vaccination has been observed in simian immunodeficiency virus (SIV)-infected rhesus macaques .
The aim of this study was to determine the impact of HAART on the antibody response to seven-valent pneumococcal conjugate vaccine (7vPnC). Further, we aimed to investigate the association between baseline CD4+ cell count, HIV viral load, and vaccine response to 7vPnC with or without a TLR9 agonist adjuvant.
This observational study was a preplanned substudy to an investigator-initiated phase Ib/IIa, randomized, double-blind, placebo-controlled trial randomizing HIV-infected adults to immunization with pneumococcal vaccines with or without CPG 7909 . The study showed that addition of CPG 7909 doubled the proportion of HIV-infected patients achieving a high vaccine-specific IgG antibody response at 9 months . The study protocols were approved by the Danish Medicines Agency, the Regional Ethical Committee, and the Danish Data Protection Agency, and registered at www.clinicaltrials.gov (NCT00562939).
Setting and participants
The study was conducted at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. The study population included HIV-seropositive volunteers aged 18 years or older. We excluded individuals who had received PPV23 immunization within the last 5 years, were on antiretroviral therapy for less than 6 months, were on antiretroviral therapy with HIV RNA more than 50 copies/ml, with CD4+ cell count less than 200 cells/μl, and were unavailable for first follow-up after first immunization. Written informed consent was obtained from all participants.
Immunization and sample collection
All participants were immunized with double the standard dose of 7vPnC (Prevnar, Wyeth) at 0 and 3 months and with one single dose of PPV23 (Pneumo Novum; Sanofi-Pasteur MSD) at 9 months. Participants were also seen at 4 and 10 months for immunogenicity and safety follow-up. One group received 1 mg CPG 7909 (formulated in 100 μl PBS buffer) added to each of their three vaccine doses, whereas the other group received PBS placebo buffer in place of CPG 7909. 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. Prior to immunization, blood samples were collected for antibody measurements and laboratory tests including HIV viral load and CD4+ cell count.
Assessment of immunogenicity
Specific IgG levels for 7vPnC serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) were analyzed in one batch using a standardized ELISA method as previously reported  by Statens Serum Institut, Copenhagen, Denmark. Serum samples were preadsorbed with optimal concentrations of pneumococcal cell wall and 22F capsular polysaccharides . Opsonophagocytic activity (OPA) of anticapsular antibodies (serotypes 6B, 14, 19F, and 23F) was measured using a flow cytometric opsonophagocytic assay giving indirect information on the antibodies' ability to opsonize and facilitate killing of invading pneumococci  by Flow Applications Inc., Illinois, USA. Serum samples were stored at −80°C before shipment for analyses.
Participants were categorized as ‘HAART-naive’ if never exposed to antiretroviral drugs or ‘HAART-treated’ if at inclusion they received either a three-drug regimen that included a nonnucleoside reverse transcriptase inhibitor, a protease inhibitor, and/or abacavir, or a two-drug regimen with a combination of a nonnucleoside reverse transcriptase inhibitor and a boosted protease inhibitor.
Baseline characteristics of the two groups were tabulated. Continuous variables were summarized using median with interquartile range. Dichotomous and categorical variables were summarized using count and percentage.
We defined 7vPnC vaccine responders as individuals with a two-fold increase in IgG levels to 1 μg/ml or more for at least five of the seven serotypes. The proportion of persistent 7vPnC vaccine responders at 9 months was our predefined endpoint. We used χ2-test to compare proportions of 7vPnC vaccine high responders at 3, 4, 9, and 10 months. Further, we calculated crude and adjusted odds ratios (aORs) for the effect of HAART on being a persistent 7vPnC vaccine responder at 9 months among all participants using logistic regression [adjusting for current smoker (yes/no), baseline CD4+ cell count (≤500/>500 cells/μl), CPG 7909 adjuvant (yes/no), BMI (≤25/>25 kg/m2), AIDS diagnosis (yes/no), and age (≤50/>50 years)]. Further, we conducted a sensitivity analysis of the effect of HAART among participants with near-normal CD4+ cell counts (>500 cells/μl). Per protocol analyses were used for all immunogenicity assessments.
Geometric means of serotype-specific IgG concentrations and OPA titers were stratified according to use of HAART. A two-way t-test was used to compare the mean loss of total vaccine-specific IgG from month 4 to month 9.
Finally, we investigated the association between baseline CD4+ cell count, HIV viral load, and vaccine response to 7vPnC with or without a TLR9 agonist adjuvant. For both HAART-naive and HAART-treated patients, we built separate linear regression models for mean 7vPnC IgG relative increase from baseline to 9 months and explored associations with baseline CD4+ cell count and HIV RNA stratified according to adjuvant group (CPG 7909 or placebo).
We used Stata software, version 9.2 (StataCorp, College Station, Texas, USA) for statistical analyses.
We included 20 HAART-naive and 75 HAART-treated persons in the study. The characteristics are described in Table 1. Fifty percent (10/20) of the HAART-naive group compared with 49% (37/75) of the HAART group received CPG 7909 as adjuvant to the pneumococcal vaccines. During follow-up, two HAART-naive patients initiated treatment between 4 and 9 months and were excluded from data analyses of PPV23 response (Supplementary Doc. 1, http://links.lww.com/QAD/A25). Six HAART-treated patients were censored after dropping out of the study (three after 3 months, one after 4 months, and two after 9 months).
Seven-valent pneumococcal conjugate vaccine responders
The proportion of 7vPnC vaccine responders in each group during the study is shown in Fig. 1. Both groups achieved significant initial responses after all three immunizations, but at the predefined primary endpoint, 6 months after the second 7vPnC, more persistent 7vPnC vaccine responders were found among HAART compared to HAART-naive (42.3 vs. 15.0%, P = 0.03), OR = 4.15 [95% confidence interval (CI) 1.11–15.4]. In an adjusted analysis, HAART use (aOR = 4.65, 95% CI 1.07–20.2) and being given a vaccine with CPG 7909 adjuvant (aOR = 3.26, 95% CI 1.24–8.58) increased the chance of being persistent 7vPnC vaccine responder at month 9, whereas baseline CD4+ cell count higher than 500 cells/μl, being current smoker, BMI higher than 25 kg/m2, AIDS diagnosis, and age older than 50 years were not significantly associated with vaccination response (Table 2). Even when the above analysis was restricted to participants with baseline CD4+ cell counts above 500 cells/μl, the measure of HAART's effect remained unchanged (aOR = 4.97, 95% CI 0.52–46.8).
Serotype-specific IgG concentrations
There were some variations in the response profiles for the 7vPnC serotypes between HAART-treated and HAART-naive (Fig. 2a). Although not statistically significant, compared to HAART-naive, HAART-treated patients tended to have a higher response to serotypes 9V, 14, and 18C, but a lower response to serotype 6B. When pooling the seven serotypes, the mean loss of total vaccine-specific IgG from the peak response at month 4 to follow-up at month 9 was significantly greater among HAART-naive than among HAART-treated (54.8 vs. 38.1%, P = 0.001) patients. Boosting with PPV23 did not increase 7vPnC IgG concentrations to levels above those observed 1 month after the second 7vPnC in either group.
Both HAART-naive and HAART-treated had substantial serotype-specific OPA increases following immunization (Fig. 2b). However, 1 month and 6 months after second 7vPnC vaccination, geometric mean OPA titers were higher among those on HAART compared with HAART-naive (statistically significant for serotypes 14, 19F, and 23F). These differences remained significant even with adjustment for baseline CD4+ cell count (data not shown). Boosting with PPV23 increased OPA titers for serotypes 6B, 19F, and 23F to levels above those observed following the second 7vPnC. However, the response curves for serotype 14 showed initial decreases following PPV23 in both groups, which were not observed for the other serotypes.
Effect of CD4+ cell count and HIV RNA on the Toll-like receptor 9 adjuvant
We found no significant difference in the effect of CPG 7909 on mean 7vPnC IgG-fold increase (from baseline to month 9) between the HAART-treated and HAART-naive patients. We found no significant effect of baseline CD4+ cell count on mean 7vPnC IgG-fold increase from baseline to month 9 in either of the two groups (data not shown). However, among HAART-naive patients who received a vaccine with CPG 7909 as adjuvant, mean 7vPnC IgG increased 2.2-fold (95% CI 1.5–3.3) per log10 HIV RNA decrease (Fig. 3). This effect of HIV RNA was specific for untreated patients receiving CPG 7909 and was not observed among HAART-naive who received a placebo adjuvant.
In this study, we found that HAART and HAART-naive HIV-infected adults with moderate to high CD4+ cell counts had similar vaccine responses initially, but persons on HAART achieved a more durable antibody response of higher magnitude and functional activity following pneumococcal conjugate vaccination than HAART-naive persons, even after adjustment for CD4+ cell count. Thus, HAART-naive patients had greater quantitative loss of vaccine-specific antibodies during follow-up than HAART-treated patients. Further, we found that TLR9-stimulated antibody production correlated negatively with plasma HIV RNA, which indicates that TLR9 adjuvants may not be useful for preventive or therapeutic vaccines in viremic HIV patients.
One of the strengths of this study was the inclusion of both quantitative and functional antibody response as endpoints. Although related, these two parameters reflect different aspects of the immunization response. The ELISA measures total binding IgG antibodies to the capsular antigen, whereas the OPA measures functional activity of the IgG antibody, but clinical data on their correlation with protection against pneumococcal disease in adults are missing. The World Health Organization considers both measurements to be equally important in the evaluation and introduction of new pneumococcal vaccines . This was the first study to evaluate and compare the effect of TLR9 agonist adjuvants in HAART-treated and HAART-naive patients, which allowed us to study the effect of TLR9 stimulation in vivo in viremic HIV patients.
When should persons with HIV be immunized? We found an almost three-fold higher proportion of persistent 7vPnC vaccine responders among HAART-treated compared to HAART-naive individuals. This finding is in line with other recent reports [29,30]. HAART use concurrent with hepatitis B vaccination is associated with a two-fold increased probability of responding to the vaccine . Further, we observed a faster decline in IgG concentrations following pneumococcal conjugate vaccination among HAART-naive compared to HAART-treated patients. This has also been reported following PPV23 in HAART-naive patients  and may be because of the increased turnover of memory B cell in untreated compared with treated HIV patients [15,16]. Only one randomized trial of PPV23 vaccination with clinical endpoints among persons with HIV has ever been conducted. The trial that was conducted among HAART-naive adults in Uganda revealed that there was no increased protection against pneumococcal disease among vaccinees . Interestingly, as demonstrated by adjusted logistic regression and sensitivity analyses, the effect of HAART on vaccine responses cannot be fully explained by differences in CD4+ cell counts. Thus, the increased loss of protective antibodies over time among HAART-naive compared to HAART-treated patients indicates that re-immunization should be conducted after commencement of HAART to achieve optimal and durable protection.
In our unadjusted regression analysis, being current smoker compared with current nonsmoker was associated with a decreased chance of having a persistent vaccine response at 9 months. In the adjusted analysis, the estimate remained similar, but was no longer statistically significant. Others have also observed a negative impact of smoking on pneumococcal vaccination responses . Thus, promoting smoking cessation among HIV patients not only may have a significant impact on their risk of pneumonia  but may also improve the effect of pneumococcal vaccination.
The benefit of combined schedules of pneumococcal conjugate and pneumococcal polysaccharide vaccines is debated . In our study, post-PPV23 IgG concentrations were similar or lower for all 7vPnC serotypes compared with IgG concentrations after second 7vPnC. Others have made comparable observations in different settings , but it remains unknown why we are unable to demonstrate a quantitative booster-effect after 7vPnC in adults, as has been observed in infants. However, looking at OPA titers, it appears that at least for serotypes 6B, 19F, and 23F, the PPV23 booster does seem to have a positive effect, whereas titers for serotype 14 seemed to decrease. A similar OPA response pattern for serotype 14 was observed in a study among children and young adults with sickle cell disease , indicating that vaccine-induced OPA increases for serotype 14 may have a different response profile than the other 7vPnC serotypes. Until recently, OPA was not used in clinical trials because it was technically difficult to perform. Therefore, the clinical significance of OPA titers is not well established, but there are indications that OPA may be better in predicting cross-protection than ELISA measurements. Clinical experience shows that 7vPnC does not induce cross-protection against serotype 19A  and correspondingly OPA titers remain low, whereas levels of antibody measured by ELISA increase . Thus, OPA may be a more accurate reflection of clinical vaccine effectiveness and boosting with 7vPnC or PPV23 may be of considerable value.
The clinical effect of pneumococcal conjugate vaccination in HIV-infected adults is unknown, but hyporesponsiveness – which complicates repeated immunizations with polysaccharide vaccines – does not appear to be an issue with conjugated vaccines . If pneumococcal conjugate vaccines were shown to be clinically effective against pneumococcal disease in adults, they might be more suitable for people with HIV.
We also found that TLR9-stimulated antibody production correlated negatively with plasma HIV RNA. HIV-induced TLR9 stimulation has recently been suggested as a potential driver of chronic immune activation and disease progression . If so, downregulation of TLR9 expression and/or signaling would be a way for the immune system to counteract this pathogenic activation of TLR9. Nowroozalizadeh et al.  demonstrated by whole-blood stimulation that TLR9 responsiveness is decreased in HAART-naive HIV-1-infected compared to HIV-negative individuals and that decreasing responsiveness was positively correlated to increasing viral load. An association between viral load and responsiveness to TLR9 agonist-adjuvanted hepatitis B vaccination was also seen in SIV-infected rhesus macaques – where monkeys with viral loads more than 107 copies/ml were unable to mount an antibody response upon immunization . Thus, individuals with moderate to high level of HIV RNA may not be very susceptible to TLR9 stimulation. This has at least two important implications: TLR9 adjuvants may not be useful for preventive or therapeutic vaccines in viremic HIV patients and these individuals may be more likely to acquire severe infections (like invasive pneumococcal disease ) in which TLR9 signaling is needed in the early stages of the host defense to control infection.
In conclusion, concomitant use of HAART improves and prolongs the antibody response to pneumococcal conjugate vaccines in persons with HIV infection, independently of CD4+ cell count at the time of immunization. Immunization or re-immunization should be conducted after commencement of HAART to achieve optimal and durable protection. Further, the interference of HIV viremia with TLR9-stimulated antibody production may have important implications for the choice of adjuvant in preventive and therapeutic vaccines for HAART-naive persons. More studies are needed to determine the mechanisms responsible for the complex interaction between chronic infection and innate and adaptive immune responses.
The authors thank the participants for their involvement in the trial. They also thank the study nurses, Iben Loftheim and Inge Arbs, for their excellent work as trial site coordinators for the study; Coley Pharmaceutical Group (now part of Pfizer) for providing CPG 7909 for the study; Statens Serum Institut, Copenhagen and Flow Applications Inc., Illinois, USA for conducting the antibody analyses. Grant support by Aarhus University, the Augustinus Foundation, Scandinavian Society for Antimicrobial Chemotherapy, Danielsen's Foundation, AP Moeller's Foundation, Krista and Viggo Pedersen's Foundation, LF Foght's Foundation, KA Rohde, and Hustru's Foundation. Coley Pharmaceutical Group (now part of Pfizer) provided CPG 7909 for the study.
Author contributions: O.S.S., N.L., H.C.S., and L.Ø. designed the study. O.S.S., A.R.B., Z.B.H., and T.A.R. contributed to patient enrolment, monitoring, and data collection. O.S.S. was responsible for database management. O.S.S. and N.L. performed the statistical analyses. O.S.S. wrote the first draft of the paper. O.S.S. and N.L. revised the paper after critical comments from all authors. All authors have read and approved the final version of the text as submitted to AIDS.
The study was presented in part at the 17th Conference on Retroviruses and Opportunistic Infections in San Francisco, 16–19 February 2010 (abstract 813).
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highly active antiretroviral therapy; HIV; immunogenicity; immunologic adjuvants; pneumococcal vaccines
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