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.
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