Conjugate and polysaccharide pneumococcal vaccines do not improve initial response of the polysaccharide vaccine in HIV-infected adults
Peñaranda, Mariaa; Payeras, Antonib; Cambra, Anac; Mila, Joanc; Riera, Melciora; the Majorcan Pneumococcal Study Group
aInfectious Diseases Division, Internal Medicine Department, Son Dureta University Hospital, Spain
bInternal Medicine Department, Son Llatzer Hospital, Spain
cImmunology Department, Son Dureta University Hospital, Palma de Mallorca, Spain.
Received 13 December, 2009
Revised 5 February, 2010
Accepted 10 February, 2010
Correspondence to Maria Peñaranda, Physician, Infectious Diseases Division, Internal Medicine Department, Son Dureta University Hospital, Palma de Mallorca, Spain. Tel: +34 971175371; fax: +34 971175228; e-mail: email@example.com
This is a randomized trial to compare the immunoglobulin G response and the antibody avidity after two pneumococcal vaccinations, conjugated pneumococcal vaccine (CPV) and polysaccharide pneumococcal vaccine (PPV) 4 weeks after vs. PPV alone in 202 HIV-infected adults. There were no differences in the two strategies, either in the percentage of immunoglobulin G two-fold increase for the CPV included serotypes or immunoglobulin G two-fold increase, reaching the level of 1 μg/ml except for serotype 23F (26% responded after conjugated pneumococcal vaccine + PPV vs. 14% after PPV). No avidity increases were seen in any strategy.
The polysaccharide pneumococcal 23-valent vaccine (PPV) is recommended for HIV-infected patients and has shown to be immunogenic in this population ; moreover, in those with a CD4 cell count above 200 cells/μl and those under HAART , although its clinical effectiveness is still controversial. The immunogenicity of the conjugated pneumococcal vaccine (CPV) has been widely demonstrated in children [3–6] but with no advantage over PPV in elderly , or immunosuppressed populations . Studies in HIV-infected adults with both vaccines found a superior response with the CPV in antibody concentration [9,10] and in functional activity , although others found no difference .
The main objective of our study was to determine whether a pneumococcal vaccination strategy combining the CPV followed by the PPV produce higher levels of specific immunoglobulin G (IgG) antibodies against the CPV included serotypes, as compared with the recommended PPV in HIV-infected adults with moderate immunosuppression. Secondary objectives were to determine those factors associated with pneumococcal vaccination response, to compare the antibody avidities before and after vaccination and between the two vaccination strategies, to assess the correlation between avidity and antibody concentration, and finally to evaluate the safety of both vaccines.
A randomized, open label and multicentric study was conducted between December 2007 and April 2008 including those HIV-infected adults who were never vaccinated against Streptococcus pneumoniae with moderate immunosuppression (CD4 cell count between 200 and 500 cells/μl) and a HIV viral load under 5 log copies/ml, from two Spanish hospitals, Son Dureta Hospital and Son Llatzer Hospital. Patients allocated to group 1 received one dose of CPV and one dose of PPV after 4 weeks. Patients allocated to group 2 received a single dose of PPV.
Blood samples were extracted before CPV (basal), before PPV (4weeks), and at 8 weeks in patients allocated in the group 1; and before PPV (basal) and at 4 weeks in patients allocated to group 2. Secondary adverse events due to both vaccines were recorded by telephone interview 3 days after the vaccination.
IgG against the CPV included serotypes, which was performed in all the samples using the methodology described by Wernette et al. . Avidity for each antibody was also determined in all the samples using the methodology described by Romero-Steiner et al. . The percentage of responders to each serotype in both groups at 8 weeks were compared using two vaccination response criteria: the first was specific antibody duplication and the second was specific antibody duplication, reaching the level of 1 μg/ml.
A total of 220 HIV-infected adults were randomized to receive CPV along with PPV 4 weeks after (n = 110) or to receive one PPV (n = 110), 18 patients were lost to follow-up, eight in group 1 and 10 in group 2. Finally, 202 patients were included in the analysis at 4 weeks (n = 102 and 100) and 198 in the analysis at 8 weeks (n = 98 and 100). Median age was 44 years in both groups and 72% were men, there were no differences between the two vaccination groups in the following variables: tobacco (61% in group 1 and 56% in group 2 were smokers), alcohol (14% and 20%), CD4 cells count at inclusion (368 and 351 cells/μl), nadir CD4 cells count (158 and 155 cells/μl), undetectable viral load at inclusion (82% and 80%), C-HIV stage (39% and 35%), HIV transmission mechanism (37% and 27%, IDU), cotrimoxazole prophylaxis (16% and 15%), previous pneumonia episodes (23% and 21%), chronic obstructive pulmonary disease (8% and 5%), hepatitis B (6 and 6%) or hepatitis C coinfection (45% and 33%). By contrast, 98% of patients in group 1 were taking HAART vs. 91% in group 2 (P = 0.027), and two patients in group 1 vs. eight patients in group 2 were cocaine users (P = 0.046).
The 34% of patients receiving CPV complained of secondary effects vs. 20% receiving PPV (P = 0.07), all mild and self limited. The most frequent were local pain (20% after CPV vs. 12% after the PPV), fever (6% vs. 3%), and asthenia and myalgias (6% vs. 3%). The geometric mean concentration of specific antibodies was similar in the two vaccination groups as pre vaccination after 4 and 8 weeks. As taking the first response criteria (duplication of specific antibodies at week 8) and the second response criteria (duplication of specific antibodies and IgG ≥1 μg/ml at week 8), there were no differences between the two strategies except for serotype 23F when the second response criteria was used in which 26% of patients who received two vaccines responded vs. 14% of patients who received the PPV [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.07–4.56, P = 0.03] Tables 1 and 2.
In the bivariate and the multivariate linear regression taking duplication and IgG at least 1 μg/ml to a minimum of four serotypes as response criteria solely nadir CD4 cells count of at least 200 cells/μl (OR 2.34, 95% CI 1.14–4.81, P = 0.02) and not reporting previous pneumonia (OR 3.05, 95% CI 1.01–9.18, P = 0.04) were associated with response. Also, not reporting previous pneumonia was the only variable associated with response to a minimum of three serotypes in the bivariate and multivariate linear regression (OR 2.90, 95% CI 1.30–6.46, P = 0.01). No variable was associated with response to a minimum of five serotypes.
Before vaccination, the avidity indexes were very heterogeneous in each serotype (from 10% to 100%). No increases in avidity after 8 weeks were seen for any serotype in both vaccination groups. There was no correlation between avidity and antibody concentration either before vaccination or at 4 or 8 weeks for any serotype.
Although the present study only reflects the initial response to the two vaccination strategies, the CPV followed by PPV showed no advantage over the recommended PPV in IgG concentration or avidity against the CPV included serotypes in HIV-infected adults with moderate immunosuppression. Nevertheless, more interesting will be the persistence of specific antibodies in each group, the interval at which antibodies decrease to the prevaccine level and whether it could be a good indicator for revaccination. We can conclude that a sequential vaccination with both vaccines, CPV and PPV, does not improve, in terms of specific antibodies and avidity, the PPV in HIV-infected patients. As more data are known, CPV should not be recommended instead of PPV in this population.
Grant of the Funds in Sanitary Investigation of Spain (FISS), Instituto de Salud Carlos III (reference number PI070268).
Majorcan Pneumococcal Study Group: Bassa A, Cambra A, Campins A, Carratala C, Cifuentes C, Frontera G, García M, Hernandez RM, Homar F, Leyes M, Liebana A, Mila J, Morey C, Murillas M, Ortiz A, Pareja A, Payeras A, Peñaranda M, Ramirez A, Roca A, Ribas MA, Riera M, Samperiz G, Serra A, Serrano A, Villalonga C, Villoslada A.
Trial number: NCT00999739.
There are no conflicts of interest.
1. Falcó V, Jordano Q, Cruz MJ, Oscar L, Esteve R, Magda C, et al
. Serological response to pneumococcal vaccination in HAART-treated HIV-infected patients: one year follow-up study. Vaccine 2006; 24:2567–2574.
2. Rodriguez-Barradas MC, Alexandraki I, Nazir T, Foltzer M, Musher DM, Brown S, Thornby JL. Response of human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy to vaccination with 23-valent pneumococcal polysaccharide vaccine
. Clin Infect Dis
3. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al
. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2009; 19:187–195.
4. Millar EV, O'Brien KL, Bronsdon MA, Madore D, Hackell JG, Reid R, Santosham M. Anticapsular serum antibody concentration and protection against pneumococcal colonization among children vaccinated with 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44:1173–1179.
5. Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al
. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344:403–409.
6. Madhi SA, Klugman KP, Kuwanda L, Cutland C, Kayhty H, Adrian P. Quantitative and qualitative anamnestic immune responses to pneumococcal conjugate vaccine in HIV-infected and HIV-uninfected children 5 years after vaccination. J Infect Dis 2009; 199:1168–1176.
7. Goldblatt D, Southern J, Andrews N, Ashton L, Burbidge P, Woodgate S, et al
. The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50–80 years. Clin Infect Dis 2009; 49:1318–1325.
8. Stanford E, Print F, Falconer M, Lamden K, Ghebrehewet S, Phin N, et al
. Immune response to pneumococcal conjugate vaccination in asplenic individuals. Hum Vaccin 2009; 5:85–91.
9. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering PH, van Furth R. Enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine in HIV-infected adults. Vaccine 2000; 19:886–894.
10. Lesprit P, Pédrono G, Molina JM, Goujard C, Girard PM, Sarrazin N, et al
. Immunological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS 2007; 21:2425–2434.
11. Feikin DR, Elie CM, Goetz MB, Lenox JL, Carlone GM, Romero-Steiner S, et al
. Specificity of the antibody response to the pneumococcal polysaccharide and conjugate vaccines in human immunodeficiency virus-infected adults. Clin Diagn Lab Immunol 2004; 11:137–141.
12. Ahmed F, Steinhoff MC, Rodriguez-Barradas MC, Hamilton RG, Musher DM, Nelson KE. Effect of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. J Infect Dis 1996; 173:83–90.
13. Wernette CM, Frasch CE, Madore D, Carlone G, Goldbatt D, Plikaytis B, et al
. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol 2003; 10:514–519.
14. Romero-Steiner S, Holder PF, Gomez de Leon P, Spear W, Hennessy TW, Carlone GM. Avidity, determinations for Haemophilus influenzae
type b anti-polyribosylribitol phosphate Antibodies. Clin Diagn Lab Immunol 2005; 12:1029–1035.
This article has been cited 4 time(s).
International Journal of Std & AIDSImmunization against pneumococcal disease in HIV-infected patients: conjugate versus polysaccharide vaccine before or after reconstitution of the immune system (CTN-147)International Journal of Std & AIDS
American Journal of TransplantationUse of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults With Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP)American Journal of Transplantation
Human Vaccines & ImmunotherapeuticsSerologic response to primary vaccination with 7-valent pneumococcal conjugate vaccine is better than with 23-valent pneumococcal polysaccharide vaccine in HIV-infected patients in the era of combination antiretroviral therapyHuman Vaccines & Immunotherapeutics
VaccineImmunogenicity and safety of pneumococcal conjugate polysaccharide and free polysaccharide vaccines alone or combined in HIV-infected adults in BrazilVaccine
© 2010 Lippincott Williams & Wilkins, Inc.