Antibody response to S.pneumoniae after vaccination with the 23-valent pneumococcal polysaccharide vaccine versus 7-valent conjuga
http://www.100md.com
Elisa García Vázquez1,Jordi Yagüe1,Felip
参见附件。
Antibody response to S.pneumoniae after vaccination with the 23-valent pneumococcal polysaccharide vaccine versus 7-valent conjugate vaccine in HIV patients with nadir CD4 count≥200 cells/μl(pdf)
Hospital Clinic. Barcelona. Spain
Correspondence to Dr. Elisa García Vázquez,Servicio de Medicina Interna-Infecciones,Hospital Universitario Virgen de la Arrixaca,Ctra. Madrid-Cartagena
30120 El Palmar (Murcia)
Tel:00 34 968 36 95 00,Fax:00 34 968 36 96 78
E-mail:elisag@eresmas.net
[Abstract] Objective To assess antibody response to capsular polysaccharides after vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV) compared to that of 7-valent conjugate vaccine (CV).Methods 149 HIV positive patients (nadir CD4 count≥200 cells/μl) were randomised into: a) PPV (n=75); or b) CV (n=74). Blood samples were obtained prior to and 4 weeks after vaccination and levels of pneumococcal capsule-specific IgG antibody were measured by an ELISA test. “Seroconversion” was defined as an increase in antibody titers >395 U/ml. End point was rate of seroconversion in each group. Results 65/149 patients (43.6%) were seroconverters. There was a trend to higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08). In multivariate analysis, factors associated with increased rate of immunogenic response to vaccination included having received PPV (OR 2.75; 95% CI 1.27~5.93) and undetectable prevacunal viral load (VL) (OR 3.30; 95% CI 1.39~7.84). After vaccination, an increase in mean VL (2.42 log. vs 2.69;P=0.004) and in mean CD4 count (627 cells/μl vs. 679;P=0.03) were observed.Conclusions Rate of seroconversion to pneumococcal vaccine is higher in PPV group than in CV group in HIV positive patients with nadir CD4 count≥200 cells/μl (OR 2.75). Immunization of HIV infected patients when VL is undetectable improves antibody response.
[Key words] HIV; pneumococcal vaccination; polysaccharide vaccine; conjugate vaccine
INTRODUCTION
In recent years, both morbidity and mortality due to opportunistic infections in HIV positive patients have greatly decreased.That thanks to highly active antiretroviral therapy (HAART). Nevertheless, infection with S.treptococcus pneumoniae is the most common cause of bacterial pneumonia among HIV infected patients in most developed countries[1~4].It has been estimated to occur 100 times more frequently in these patients than in general population (8~10 cases per 1000 patients/year),and the incidence is even higher in HIV positive patients who are also drug users and/or alcoholics[5,6].Recurrence is relatively common (13% of cases within 6 month, 6~7 times higher than in HIV negative patients)[7] and mortality rate is similar to that in non-HIV patients (5%~11%)[8], depending on severity at admission.
The Centers for Disease Control and Prevention (CDC) recommend immunization with a single dose of polysaccharide pneumococcal vaccine in HIV infected adolescents and adults who have a CD4 T lymphocyte count of≥200 cells/μl[9].
In Spain, there are available two different types of pneumococcal vaccine: a) 23-valent polysaccharide pneumococcal vaccine (Pneumo23, Aventis Pasteur MSDa and Pnu-Imune de Wyeth Lederle);and b) 7-pneumococcal glycoprotein conjugate vaccine (Prevenir, Wyeth Lederle).
The former contains 23 of the commoner serotypes of S. pneumoniae, covering around 90% of invasive infections. Its efficacy is probably 70% in preventing pneumococcal pneumonia but less in presence of immunosuppression. It is the recommend vaccine in people over 65 years old and persons at the high risk of pneumococcal infection due to comorbidity, such as HIV infection. Humoral response to polysaccharide antigens tend to be mainly T-lymphocyte independent and B-lymphocyte mediated[10].Unfortunately, although HIV infection mainly determines cellular immune defects, it also contributes to humoral immune abnormalities and some authors[11，12],have documented a reduced immunogenicity of this vaccine in HIV infected persons, which creates a need for a more immunogenic vaccine.
The conjugate vaccine is recommended in children under 2 years, as they lack the mature B lymphocytes necessary for T cell-independent antibody mediated immunity. The conjugation of T cell-independent polysaccharide antigens to proteins is believed to confer the properties of T cell-dependent antigens to the polysaccharide and it has been suggested that this vaccine might be more immunogenic in individuals with the poorest immune response to polysaccharide vaccine[13~17].
As the immune response to CV is T-lymphocyte dependent, it might be assumed that the humoral response to this vaccine is lower in HIV positive patients. The aim of this study is to compare the immunogenicity of the 7-conjugate pneumococcal vaccine (CV group) with that of the 23-valent pneumococcal polysaccharide vaccine (PPV group) and to evaluate if HIV infection, assessed by CD4 counts and viral load, modifies the immune response to the vaccine.
PATIENTS AND METHODS
HIV infected patients were recruited from our outpatients clinic cohort at Hospital Clinic (Barcelona) from September 2002 to April 2003.
Only patients with CD4 counts before vaccination≥200 cells/μl were included in the study. All patients were under HAART. Patients with a CD4 count nadir < 200 cells/μl and those who had been immunized with a pneumococcal vaccine in the previous 3 years were excluded. Patients could not received any other immunization within 30 days after PV administration. Patients provide their informed consent to participate in the study and the guidelines for experimental investigation with human subjects required by our institution were followed.
Clinical data (sex, age, risk factor for HIV infection, date of diagnoses and time on antiretroviral treatment) were registered as well as data regarding previous CD4 counts and viral loads. Immunoglobulin isotype concentrations and IgG subclasses were measured before vaccination and CD4 count and viral load was measured 4 weeks after vaccination.
Patients were open label randomised into received either: a) PPV (Pneumovax; Merk), a 23-valent preparation containing 25 μg of each of the following capsular polysaccharides: types 1~5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F (PPV group) or b) CV (Pnu-Imune; Wyeth Lederle), a 7-valent pneumococcal conjugate containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (CV group).
Venous blood was collected before and 4 weeks after immunization. Blood samples were centrifuged at 3000 rpm for 15 minutes and the resulting sera were stored in aliquots frozen at-20 ℃ until studied. Total Ig G levels specific to S. pneumoniae were determined by an ELISA test based on the method described by Metzger,et al.[18] but modified by using the pneumococcal vaccine as antigen as described by Siber,et al.[19,20].The results of total antipneumococcal IgG were expressed as arbitrary units using a reference serum of 2240 U/ml calibrated against a pneumococcal reference preparation with the assigned value of 70 U/ml pneumococcal IgG antibody from the European Quality Scheme for specific antibodies (Oxfordshire Health Authority, John Radcliffe Hospital; Oxford, UK), donated by Dr. MJ Rodrigo (Hospital Vall d'Hebron, Barcelona, Spain). For specific total IgG, the minimal amount of antibody detectable with this assay was 0.11 U/ml and within-run and day-to-day coefficients of variation were 7.6% and 10.5%, respectively. A “seroconverter” to the PV was defined as an individual showed an increase in his/her antibody titers >395 U/ml.
Sample size calculations, based on a 50% rate of immunological response to polysaccharide pneumococcal vaccine in HIV patients with CD4 counts≥200 cells/μl, a significance level of 0.05, and a power of 0.90, indicated that 74 patients would need to be vaccinated with each vaccine (PPV group and CV group) to detect a difference of > 25 % in the proportion of “seroconverters”.
Intergroup means were compared by Students's t test and proportions by the c2 statistic. To assess the independent relation of the different variables with seroconversion, a nonconditional stepwise logistic regression procedure with seroconversion as dependent variable was done.
All statistical values were calculated using the SPSS 9.0 software package.
RESULTS
A total of 149 HIV positive patients were included in the study: 75 in PPV group and 74 in CV group. 102 patients (68.5%) were male and 47 (31.5%) female. Distributions according to risk factors for HIV infection are detailed in Table 1. Distributions of risk factors for HIV infection and potentially confounding variables were similar between the 2 vaccine groups except for follow-up time since diagnoses (Table 2).
Table 1 Risk Factor for HIV Infection n(%)
MSM: men having sex with men
Sixty five out of 149 patients were seroconverters (43.6%). There was a trend to have a higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08).
Table 2 Comparability of Subjects According to Vaccine Type Mean (SD)
Continued
Note:ART: antiretroviral treatment CD4 increase=(pre-vaccination CD4 count-lowest CD4 count)/lowest CD4 count
Factors associated with immunological response to pneumococcal vaccine in the univariate analysis are detailed in Table 3. In a multivariate analysis, factors associated with an increased rate of immunogenic response to pneumococcal vaccine included having received PPV (OR 2.75; 95% CI 1.27~5.93), undetectable prevacunal VL (OR 3.30; 95% CI 1.39~7.84) and a shorter time of HIV diagnoses (OR per each year 0.89; 95% CI 0.82~0.96) (Table 4).
Table 3 Factors Associated with Immunological Response to Pneumococcal Vaccine (Univariate Analysis)
Note:ART: antiretroviral treatment
Table 4 Variables Independently Associated with Immunological Response to Pneumococcal Vaccine (Logistic Regression Analysis)
After vaccination, an increase in mean viral load (VL) (2.69 log. vs 2.42;P=0.004) and in mean CD4 count (679 cells/μl vs. 627;P=0.03) were observed when compared to those values before vaccination.
DISCUSSION
Since S. pneumoniae infeccion remains the most common cause of bacterial pneumonia among HIV infected persons, primary or secondary prophylaxis with a vaccine could be of great usefulness. Nevertheless, there is a need for a more immunogenic vaccine, as many of these individuals exhibit a very poor immune response to vaccination. Thus, in our study only 65 out of 149 patients were seroconverters (43.6%), compared to rates of humoral response over 70% in general population.
The antibody response elicited by conjugate vaccines in HIV-uninfected adults seems to be higher to that of polysaccharide vaccines[21]. However, in HIV positive patients, data are not conclusive. Crohn,et al.[22]showed an enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine. In another study, antibody responses to H. influenzae type b vaccines (conjugate vaccine) was greater than that to non-conjugate ones[23].But Ahmed F,et al.[21] found that conjugate pneumococcal vaccine antibody response was higher compare to non-conjugate vaccine in general population and in HIV positive patients whose CD4 counts were≥de 500 cells/μl but lower and similar independently of vaccine type in HIV positive patients with CD4 counts below 500 cells/μl. The pneumococcal capsular polysaccharide antigens included in the PPV induce a T-lymphocyte independent antibody response whereas the conjugate vaccine is more immunogenic but needs a T cell dependent mechanism to produce anti-pneumococcal antibodies. In our study there was a trend to have a higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08) and in the multivariate analysis, having received PPV (OR 2.75; 95% CI 1.27~5.93) was associated with an increased rate of immunogenic response to pneumococcal vaccine. This finding is probably related to the fact that humoral responses to polysaccharide antigens tend to be mainly T-lymphocyte independent whereas conjugation confers the properties of T cell-dependent antigens to the polysaccharide and HIV patients have an impaired cellular immunity.
Different studies have pointed that immunization soon after seroconversion rather than later, when nadir CD4 counts are≥500 cells/μl appears to improve antibody responses[24~30].In our study, undetectable pre-vaccination viral load was associated both in the univariate analysis and in the logistic regression with an increased rate of immunogenic response to PV (OR 3.30; 95% CI 1.39~7.84). A shorter time since HIV diagnoses was also associated with a higher rate of seroconversion (OR per each year 0.89; 95% CI 0.82~0.96). These findings underscores the need to immunize HIV-infected patients when their viral load is undetectable and early in the course of their infection with currently available polysaccharide vaccines.
In our study,there was an increased in mean viral load after vaccination compared to that prior to vaccination (2.42 log. vs 2.69;P=0.004), but also in mean CD4 count (627 cells/μl vs. 679;P=0.03). This effect in viral load has also been reported by different authors[31~32] who documented how certain vaccines (pneumococcal,influenza,tetanus)represent an immunological stimulus that triggers viral load although the effect is not long-lasting. However, our protocol was not design to analyse this aspect and other factors influencing viral load and CD4 counts (e.g adherence to antiretroviral drugs) might be interfering in the results.
In conclusion, rate of seroconversion to PV is higher in PPV group than in CV group in HIV positive patients with CD4 counts ≥200 cells/μl (OR 2.75). Immunization of HIV infected patients when viral load is undetectable improves antibody response.
ACKNOWLEDGEMENTS
We thank to all staff in the outpatients clinics, meanly to the nurses, without whom this study could not have been possible. And also to the HIV positive patients cohort at our clinics, for their collaboration and willingness to participate in the study.
REFERENCES
1. Barlett JG. Pneumonia in the patient with HIV infection. Infect Dis Clin North Am, 1998,12:807-820.
2. Wolff AJ, O′Donnell A. Pulmonary manifestations of HIV infection in the era of highly active antirretroviral therapy. Chest,2001,120:1888-1893.
3. Tumbarello M, Tacconelli E, Gaetano KD,et al.HIV associated bacteremia: how it has changed in the HAART era. J Acquired Immune Defic Synd, 2000,23:145-151.
4. Turett GS, Blum S, Telzak EE. Recurrent pneumococcal bacteremia: risk factors and outcomes. Arch Intern Med,2001,161:2141-2144.
5. Mundy LM, Auwaerter PG, Oldach D,et al.Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med, 1995,152:1309-1315.
6. Dworkin MS, Ward JW, Hanson DL,et al.Pneumococcal Disease among Human Immunodeficiency Virus-Infected Persons: incidence, risk factors and impact of vaccination. Clin Infect Dis, 2001,32:794-800.
7. McEllistrem MC, Mendelsohn AB, Pass MA,et al.Recurrent invasive pneumoccocal Disease in Individuals with HIV infection. J Infect Dis,2002,185:1364-1368.
8. Feldman C, Glatthaar M, Morar R,et al.Bacteremic pneumococcal pneumonia in HIV-seropositive and HIV-seronegative adults. Chest,1999,116:107-114.
9. Centers for Disease Control and Prevention. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV: US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). MMWR Morb Mortal Wkly Rep,1999,48(RR-10):1-59;61-66.
10. Mond JJ, Lees A, Sanpper CM. T cell-independent antigens type 2. Ann Rev Immunol,1995,13:665-92.
11. Janoff EN, Douglas JM, Gabriel M,et al. Class-specific antibody responses to pneumococcal capsular polysaccharides in men infected with HIV type Ⅰ. J Infect Dis,1988,158:983-990.
12. Pinching AJ. Antibody responses in HIV infection. Clin Exp Immunol,1991,84:181-184.
13. Giebink GS.The prevention of pneumococcal disease in children. N Engl J Med,2001,345:1177-1183.
14. Spoulou V, Gilks CF, Ioannidis J P A. Protein conjugate pneumococcal vaccines. Offer new opportunities for high risk individuals but still lack robust evidence. BMJ,2002,324:750-751.
15. Black S, Shinefield H,the Kaiser Permanent Vaccine Study Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J,2000,9:187-195.
16. Zielen S, Buhring I, Stand N,et al.Immunogenicity and tolerance of a 7-valent pneumococcal conjugate vaccine in non-responders to the 23-valent pneumococcal vaccine. Infect Immun 2000,68:1435-1440.
17. Eskola J, Antilla M. Pneumococcal conjugate vacines. Pediatr Infect Dis J, 1999,18:543-51.
18. Metzger WJ, Butler JE, Swanson D, et al. Amplification of the enzyme-linked immunosorbent assay for measuring allergen-specific IgE and IgG antibody. Clin Allergy,1981,11:523-531.
19. Siber GR, Priehs C, Madore DW.Standardization of antibody assays for measuring response to pneumococcal infection and immunization. Pediatr Infect Dis J,1989,8:S84-S91.
20. Rodrigo MJ, Miravitlles M, Cruz MJ, et al. Characterization of specific immunoglobulin G (IgG) and its subclasses (IgG1 and IgG2) against the 23-valent pneumococcal vaccine in a healthy adult population: proposal for response criteria. Clin Diag Lab Immunol,1997,4:168-172.
21. Ahmed F, Steinhoff MC, Rodríguez-Barradas MC,et al.Effect of HIV type I infection on the antibody response to glycoprotein conjugate pneumococcal vaccine: results form a randomized trial. J of Inf Dis,1996,173:83-90.
22. Crohn FP, van Dissel TJ, Ravensbergen E,et al.Enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine in HIV-infected adults. Vaccine,2000,19:886-894.
23. Steinhoff MC, Auerbach BS, Nelson KE,et al.Antibody responses to H. influenzae type b vaccines in men with HIV infection. N Engl J Med,1991,325:1837-1842.
24. Rodríguez Barradas MC, Musher DM, Lahart C,et al.Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine. J.Infect Dis,1992,165:553-556.
25. Begemann M, Policar M. Pneumococcal vaccine failure in an HIV-infected patient with fatal pneumococcal sepsis and HCV-related cirrhosis. The Mount Sinai J of Med,2001,68:396-399.
26. Kroon FP, van Diessel JT, de Long JC,et al. Antibody response to influenza, tetanus and pneumococcal vaccines in HIV-1 seropositive individuals in relation to the number of CD4 lymphocytes. AIDS,1994,8:469-476.
27. Weiss PJ, Wallace MR, Oldfield III EC,et al.Response of recent HIV seroconverters to the pneumococcal polysaccharide vaccine and Haemophilus influenzae Type b conjugate vaccine. J Inf Dis,1995,171:1217-1222.
28. Nielsen H, Kvinesdal B, Benfield TL,et al.Rapid loss of specific antibodies after pneumococcal vaccination in patients with HIV-I infection. Scand J Infect Dis, 1998,30:597-601.
29. Tasker SA, Wallace MR, Rubins JB,et al.Reimmunization with 23-valente pneumococcal vaccine for patients infected with human immunodeficiency virus type 1: clinical, immunologic and virologic responses. Clin Infect Dis,2002,34:813-821.
30. Kvale D, Aaberge IS, Froland SS. Predictive value of immunologic parameters and HIV RNA in relation to humoral pneumoccal polysaccharide vaccine responses in patients with HIV infection. Eur J Clin Microbiol Infect Dis,2002,21:688-690.
31. Kolber M, Gabr A, Rosa A,et al. Genotypic analysis of plasma HIV-1 RNA alter influenza vaccination of patients with previously indetectable viral loads. AIDS,2002,16:537-542.
32. Goetz MB, Feikin DR, Lennox JL, et al.Viral load response to a pneumococcal conjugate vaccine, polysaccharide vaccine or placebo among HIV infected patients. AIDS,2002,16:1421-1423.
1 Institut d'Infeccions i Immunologia
2Unitat d'Avaluació i Prevenció
(Editor LEE)
Antibody response to S.pneumoniae after vaccination with the 23-valent pneumococcal polysaccharide vaccine versus 7-valent conjugate vaccine in HIV patients with nadir CD4 count≥200 cells/μl(pdf)
Hospital Clinic. Barcelona. Spain
Correspondence to Dr. Elisa García Vázquez,Servicio de Medicina Interna-Infecciones,Hospital Universitario Virgen de la Arrixaca,Ctra. Madrid-Cartagena
30120 El Palmar (Murcia)
Tel:00 34 968 36 95 00,Fax:00 34 968 36 96 78
E-mail:elisag@eresmas.net
[Abstract] Objective To assess antibody response to capsular polysaccharides after vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV) compared to that of 7-valent conjugate vaccine (CV).Methods 149 HIV positive patients (nadir CD4 count≥200 cells/μl) were randomised into: a) PPV (n=75); or b) CV (n=74). Blood samples were obtained prior to and 4 weeks after vaccination and levels of pneumococcal capsule-specific IgG antibody were measured by an ELISA test. “Seroconversion” was defined as an increase in antibody titers >395 U/ml. End point was rate of seroconversion in each group. Results 65/149 patients (43.6%) were seroconverters. There was a trend to higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08). In multivariate analysis, factors associated with increased rate of immunogenic response to vaccination included having received PPV (OR 2.75; 95% CI 1.27~5.93) and undetectable prevacunal viral load (VL) (OR 3.30; 95% CI 1.39~7.84). After vaccination, an increase in mean VL (2.42 log. vs 2.69;P=0.004) and in mean CD4 count (627 cells/μl vs. 679;P=0.03) were observed.Conclusions Rate of seroconversion to pneumococcal vaccine is higher in PPV group than in CV group in HIV positive patients with nadir CD4 count≥200 cells/μl (OR 2.75). Immunization of HIV infected patients when VL is undetectable improves antibody response.
[Key words] HIV; pneumococcal vaccination; polysaccharide vaccine; conjugate vaccine
INTRODUCTION
In recent years, both morbidity and mortality due to opportunistic infections in HIV positive patients have greatly decreased.That thanks to highly active antiretroviral therapy (HAART). Nevertheless, infection with S.treptococcus pneumoniae is the most common cause of bacterial pneumonia among HIV infected patients in most developed countries[1~4].It has been estimated to occur 100 times more frequently in these patients than in general population (8~10 cases per 1000 patients/year),and the incidence is even higher in HIV positive patients who are also drug users and/or alcoholics[5,6].Recurrence is relatively common (13% of cases within 6 month, 6~7 times higher than in HIV negative patients)[7] and mortality rate is similar to that in non-HIV patients (5%~11%)[8], depending on severity at admission.
The Centers for Disease Control and Prevention (CDC) recommend immunization with a single dose of polysaccharide pneumococcal vaccine in HIV infected adolescents and adults who have a CD4 T lymphocyte count of≥200 cells/μl[9].
In Spain, there are available two different types of pneumococcal vaccine: a) 23-valent polysaccharide pneumococcal vaccine (Pneumo23, Aventis Pasteur MSDa and Pnu-Imune de Wyeth Lederle);and b) 7-pneumococcal glycoprotein conjugate vaccine (Prevenir, Wyeth Lederle).
The former contains 23 of the commoner serotypes of S. pneumoniae, covering around 90% of invasive infections. Its efficacy is probably 70% in preventing pneumococcal pneumonia but less in presence of immunosuppression. It is the recommend vaccine in people over 65 years old and persons at the high risk of pneumococcal infection due to comorbidity, such as HIV infection. Humoral response to polysaccharide antigens tend to be mainly T-lymphocyte independent and B-lymphocyte mediated[10].Unfortunately, although HIV infection mainly determines cellular immune defects, it also contributes to humoral immune abnormalities and some authors[11，12],have documented a reduced immunogenicity of this vaccine in HIV infected persons, which creates a need for a more immunogenic vaccine.
The conjugate vaccine is recommended in children under 2 years, as they lack the mature B lymphocytes necessary for T cell-independent antibody mediated immunity. The conjugation of T cell-independent polysaccharide antigens to proteins is believed to confer the properties of T cell-dependent antigens to the polysaccharide and it has been suggested that this vaccine might be more immunogenic in individuals with the poorest immune response to polysaccharide vaccine[13~17].
As the immune response to CV is T-lymphocyte dependent, it might be assumed that the humoral response to this vaccine is lower in HIV positive patients. The aim of this study is to compare the immunogenicity of the 7-conjugate pneumococcal vaccine (CV group) with that of the 23-valent pneumococcal polysaccharide vaccine (PPV group) and to evaluate if HIV infection, assessed by CD4 counts and viral load, modifies the immune response to the vaccine.
PATIENTS AND METHODS
HIV infected patients were recruited from our outpatients clinic cohort at Hospital Clinic (Barcelona) from September 2002 to April 2003.
Only patients with CD4 counts before vaccination≥200 cells/μl were included in the study. All patients were under HAART. Patients with a CD4 count nadir < 200 cells/μl and those who had been immunized with a pneumococcal vaccine in the previous 3 years were excluded. Patients could not received any other immunization within 30 days after PV administration. Patients provide their informed consent to participate in the study and the guidelines for experimental investigation with human subjects required by our institution were followed.
Clinical data (sex, age, risk factor for HIV infection, date of diagnoses and time on antiretroviral treatment) were registered as well as data regarding previous CD4 counts and viral loads. Immunoglobulin isotype concentrations and IgG subclasses were measured before vaccination and CD4 count and viral load was measured 4 weeks after vaccination.
Patients were open label randomised into received either: a) PPV (Pneumovax; Merk), a 23-valent preparation containing 25 μg of each of the following capsular polysaccharides: types 1~5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F (PPV group) or b) CV (Pnu-Imune; Wyeth Lederle), a 7-valent pneumococcal conjugate containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (CV group).
Venous blood was collected before and 4 weeks after immunization. Blood samples were centrifuged at 3000 rpm for 15 minutes and the resulting sera were stored in aliquots frozen at-20 ℃ until studied. Total Ig G levels specific to S. pneumoniae were determined by an ELISA test based on the method described by Metzger,et al.[18] but modified by using the pneumococcal vaccine as antigen as described by Siber,et al.[19,20].The results of total antipneumococcal IgG were expressed as arbitrary units using a reference serum of 2240 U/ml calibrated against a pneumococcal reference preparation with the assigned value of 70 U/ml pneumococcal IgG antibody from the European Quality Scheme for specific antibodies (Oxfordshire Health Authority, John Radcliffe Hospital; Oxford, UK), donated by Dr. MJ Rodrigo (Hospital Vall d'Hebron, Barcelona, Spain). For specific total IgG, the minimal amount of antibody detectable with this assay was 0.11 U/ml and within-run and day-to-day coefficients of variation were 7.6% and 10.5%, respectively. A “seroconverter” to the PV was defined as an individual showed an increase in his/her antibody titers >395 U/ml.
Sample size calculations, based on a 50% rate of immunological response to polysaccharide pneumococcal vaccine in HIV patients with CD4 counts≥200 cells/μl, a significance level of 0.05, and a power of 0.90, indicated that 74 patients would need to be vaccinated with each vaccine (PPV group and CV group) to detect a difference of > 25 % in the proportion of “seroconverters”.
Intergroup means were compared by Students's t test and proportions by the c2 statistic. To assess the independent relation of the different variables with seroconversion, a nonconditional stepwise logistic regression procedure with seroconversion as dependent variable was done.
All statistical values were calculated using the SPSS 9.0 software package.
RESULTS
A total of 149 HIV positive patients were included in the study: 75 in PPV group and 74 in CV group. 102 patients (68.5%) were male and 47 (31.5%) female. Distributions according to risk factors for HIV infection are detailed in Table 1. Distributions of risk factors for HIV infection and potentially confounding variables were similar between the 2 vaccine groups except for follow-up time since diagnoses (Table 2).
Table 1 Risk Factor for HIV Infection n(%)
MSM: men having sex with men
Sixty five out of 149 patients were seroconverters (43.6%). There was a trend to have a higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08).
Table 2 Comparability of Subjects According to Vaccine Type Mean (SD)
Continued
Note:ART: antiretroviral treatment CD4 increase=(pre-vaccination CD4 count-lowest CD4 count)/lowest CD4 count
Factors associated with immunological response to pneumococcal vaccine in the univariate analysis are detailed in Table 3. In a multivariate analysis, factors associated with an increased rate of immunogenic response to pneumococcal vaccine included having received PPV (OR 2.75; 95% CI 1.27~5.93), undetectable prevacunal VL (OR 3.30; 95% CI 1.39~7.84) and a shorter time of HIV diagnoses (OR per each year 0.89; 95% CI 0.82~0.96) (Table 4).
Table 3 Factors Associated with Immunological Response to Pneumococcal Vaccine (Univariate Analysis)
Note:ART: antiretroviral treatment
Table 4 Variables Independently Associated with Immunological Response to Pneumococcal Vaccine (Logistic Regression Analysis)
After vaccination, an increase in mean viral load (VL) (2.69 log. vs 2.42;P=0.004) and in mean CD4 count (679 cells/μl vs. 627;P=0.03) were observed when compared to those values before vaccination.
DISCUSSION
Since S. pneumoniae infeccion remains the most common cause of bacterial pneumonia among HIV infected persons, primary or secondary prophylaxis with a vaccine could be of great usefulness. Nevertheless, there is a need for a more immunogenic vaccine, as many of these individuals exhibit a very poor immune response to vaccination. Thus, in our study only 65 out of 149 patients were seroconverters (43.6%), compared to rates of humoral response over 70% in general population.
The antibody response elicited by conjugate vaccines in HIV-uninfected adults seems to be higher to that of polysaccharide vaccines[21]. However, in HIV positive patients, data are not conclusive. Crohn,et al.[22]showed an enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine. In another study, antibody responses to H. influenzae type b vaccines (conjugate vaccine) was greater than that to non-conjugate ones[23].But Ahmed F,et al.[21] found that conjugate pneumococcal vaccine antibody response was higher compare to non-conjugate vaccine in general population and in HIV positive patients whose CD4 counts were≥de 500 cells/μl but lower and similar independently of vaccine type in HIV positive patients with CD4 counts below 500 cells/μl. The pneumococcal capsular polysaccharide antigens included in the PPV induce a T-lymphocyte independent antibody response whereas the conjugate vaccine is more immunogenic but needs a T cell dependent mechanism to produce anti-pneumococcal antibodies. In our study there was a trend to have a higher rate of seroconversion in PPV group (50.7%) than in CV group (36.5%) (P=0.08) and in the multivariate analysis, having received PPV (OR 2.75; 95% CI 1.27~5.93) was associated with an increased rate of immunogenic response to pneumococcal vaccine. This finding is probably related to the fact that humoral responses to polysaccharide antigens tend to be mainly T-lymphocyte independent whereas conjugation confers the properties of T cell-dependent antigens to the polysaccharide and HIV patients have an impaired cellular immunity.
Different studies have pointed that immunization soon after seroconversion rather than later, when nadir CD4 counts are≥500 cells/μl appears to improve antibody responses[24~30].In our study, undetectable pre-vaccination viral load was associated both in the univariate analysis and in the logistic regression with an increased rate of immunogenic response to PV (OR 3.30; 95% CI 1.39~7.84). A shorter time since HIV diagnoses was also associated with a higher rate of seroconversion (OR per each year 0.89; 95% CI 0.82~0.96). These findings underscores the need to immunize HIV-infected patients when their viral load is undetectable and early in the course of their infection with currently available polysaccharide vaccines.
In our study,there was an increased in mean viral load after vaccination compared to that prior to vaccination (2.42 log. vs 2.69;P=0.004), but also in mean CD4 count (627 cells/μl vs. 679;P=0.03). This effect in viral load has also been reported by different authors[31~32] who documented how certain vaccines (pneumococcal,influenza,tetanus)represent an immunological stimulus that triggers viral load although the effect is not long-lasting. However, our protocol was not design to analyse this aspect and other factors influencing viral load and CD4 counts (e.g adherence to antiretroviral drugs) might be interfering in the results.
In conclusion, rate of seroconversion to PV is higher in PPV group than in CV group in HIV positive patients with CD4 counts ≥200 cells/μl (OR 2.75). Immunization of HIV infected patients when viral load is undetectable improves antibody response.
ACKNOWLEDGEMENTS
We thank to all staff in the outpatients clinics, meanly to the nurses, without whom this study could not have been possible. And also to the HIV positive patients cohort at our clinics, for their collaboration and willingness to participate in the study.
REFERENCES
1. Barlett JG. Pneumonia in the patient with HIV infection. Infect Dis Clin North Am, 1998,12:807-820.
2. Wolff AJ, O′Donnell A. Pulmonary manifestations of HIV infection in the era of highly active antirretroviral therapy. Chest,2001,120:1888-1893.
3. Tumbarello M, Tacconelli E, Gaetano KD,et al.HIV associated bacteremia: how it has changed in the HAART era. J Acquired Immune Defic Synd, 2000,23:145-151.
4. Turett GS, Blum S, Telzak EE. Recurrent pneumococcal bacteremia: risk factors and outcomes. Arch Intern Med,2001,161:2141-2144.
5. Mundy LM, Auwaerter PG, Oldach D,et al.Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med, 1995,152:1309-1315.
6. Dworkin MS, Ward JW, Hanson DL,et al.Pneumococcal Disease among Human Immunodeficiency Virus-Infected Persons: incidence, risk factors and impact of vaccination. Clin Infect Dis, 2001,32:794-800.
7. McEllistrem MC, Mendelsohn AB, Pass MA,et al.Recurrent invasive pneumoccocal Disease in Individuals with HIV infection. J Infect Dis,2002,185:1364-1368.
8. Feldman C, Glatthaar M, Morar R,et al.Bacteremic pneumococcal pneumonia in HIV-seropositive and HIV-seronegative adults. Chest,1999,116:107-114.
9. Centers for Disease Control and Prevention. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV: US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). MMWR Morb Mortal Wkly Rep,1999,48(RR-10):1-59;61-66.
10. Mond JJ, Lees A, Sanpper CM. T cell-independent antigens type 2. Ann Rev Immunol,1995,13:665-92.
11. Janoff EN, Douglas JM, Gabriel M,et al. Class-specific antibody responses to pneumococcal capsular polysaccharides in men infected with HIV type Ⅰ. J Infect Dis,1988,158:983-990.
12. Pinching AJ. Antibody responses in HIV infection. Clin Exp Immunol,1991,84:181-184.
13. Giebink GS.The prevention of pneumococcal disease in children. N Engl J Med,2001,345:1177-1183.
14. Spoulou V, Gilks CF, Ioannidis J P A. Protein conjugate pneumococcal vaccines. Offer new opportunities for high risk individuals but still lack robust evidence. BMJ,2002,324:750-751.
15. Black S, Shinefield H,the Kaiser Permanent Vaccine Study Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J,2000,9:187-195.
16. Zielen S, Buhring I, Stand N,et al.Immunogenicity and tolerance of a 7-valent pneumococcal conjugate vaccine in non-responders to the 23-valent pneumococcal vaccine. Infect Immun 2000,68:1435-1440.
17. Eskola J, Antilla M. Pneumococcal conjugate vacines. Pediatr Infect Dis J, 1999,18:543-51.
18. Metzger WJ, Butler JE, Swanson D, et al. Amplification of the enzyme-linked immunosorbent assay for measuring allergen-specific IgE and IgG antibody. Clin Allergy,1981,11:523-531.
19. Siber GR, Priehs C, Madore DW.Standardization of antibody assays for measuring response to pneumococcal infection and immunization. Pediatr Infect Dis J,1989,8:S84-S91.
20. Rodrigo MJ, Miravitlles M, Cruz MJ, et al. Characterization of specific immunoglobulin G (IgG) and its subclasses (IgG1 and IgG2) against the 23-valent pneumococcal vaccine in a healthy adult population: proposal for response criteria. Clin Diag Lab Immunol,1997,4:168-172.
21. Ahmed F, Steinhoff MC, Rodríguez-Barradas MC,et al.Effect of HIV type I infection on the antibody response to glycoprotein conjugate pneumococcal vaccine: results form a randomized trial. J of Inf Dis,1996,173:83-90.
22. Crohn FP, van Dissel TJ, Ravensbergen E,et al.Enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine in HIV-infected adults. Vaccine,2000,19:886-894.
23. Steinhoff MC, Auerbach BS, Nelson KE,et al.Antibody responses to H. influenzae type b vaccines in men with HIV infection. N Engl J Med,1991,325:1837-1842.
24. Rodríguez Barradas MC, Musher DM, Lahart C,et al.Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine. J.Infect Dis,1992,165:553-556.
25. Begemann M, Policar M. Pneumococcal vaccine failure in an HIV-infected patient with fatal pneumococcal sepsis and HCV-related cirrhosis. The Mount Sinai J of Med,2001,68:396-399.
26. Kroon FP, van Diessel JT, de Long JC,et al. Antibody response to influenza, tetanus and pneumococcal vaccines in HIV-1 seropositive individuals in relation to the number of CD4 lymphocytes. AIDS,1994,8:469-476.
27. Weiss PJ, Wallace MR, Oldfield III EC,et al.Response of recent HIV seroconverters to the pneumococcal polysaccharide vaccine and Haemophilus influenzae Type b conjugate vaccine. J Inf Dis,1995,171:1217-1222.
28. Nielsen H, Kvinesdal B, Benfield TL,et al.Rapid loss of specific antibodies after pneumococcal vaccination in patients with HIV-I infection. Scand J Infect Dis, 1998,30:597-601.
29. Tasker SA, Wallace MR, Rubins JB,et al.Reimmunization with 23-valente pneumococcal vaccine for patients infected with human immunodeficiency virus type 1: clinical, immunologic and virologic responses. Clin Infect Dis,2002,34:813-821.
30. Kvale D, Aaberge IS, Froland SS. Predictive value of immunologic parameters and HIV RNA in relation to humoral pneumoccal polysaccharide vaccine responses in patients with HIV infection. Eur J Clin Microbiol Infect Dis,2002,21:688-690.
31. Kolber M, Gabr A, Rosa A,et al. Genotypic analysis of plasma HIV-1 RNA alter influenza vaccination of patients with previously indetectable viral loads. AIDS,2002,16:537-542.
32. Goetz MB, Feikin DR, Lennox JL, et al.Viral load response to a pneumococcal conjugate vaccine, polysaccharide vaccine or placebo among HIV infected patients. AIDS,2002,16:1421-1423.
1 Institut d'Infeccions i Immunologia
2Unitat d'Avaluació i Prevenció
(Editor LEE)
您现在查看是摘要介绍页，详见PDF附件。