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To evaluate whether a strategy combining a prime with a 7-valent conjugate pneumococcal vaccine (PCV) followed by a boost with the 23-valent polysaccharide vaccine (PPV) would improve immunogenicity against Streptococcus pneumoniae polysaccharides in HIV-infected patients.Randomized controlled phase II trial.Two-hundred and twelve patients with CD4 cell counts of 200–500 cells/μl and HIV RNA< 4 log10 copies/ml, regardless of antiretroviral treatment, were randomized to receive either PCV at week 0 and PPV at week 4 (n = 106) or PPV alone at week 4 (n = 106). The proportion of responders to 0, 1–2, 3–4, 5–7 serotypes shared by the two vaccines was evaluated at week 8 and compared using a proportional odds model allowing for adjustment for CD4 cell count, HIV RNA and antiretroviral treatment.At week 8, the profile of response was better in the prime-boost group compared to the PPV group, as determined by the frequency of patients who reached both a twofold increase of serotype-specific IgG levels and IgG level ≥ 1 μg/ml [proportional odds ratio (OR), 2.09; 95% confidence interval (CI), 1.25–3.51; P = 0.005]. No differences in responders were found 4 weeks after PCV or PPV alone, suggesting that PCV primed for response to PPV. Early differences between groups remained significant at week 24 (proportional OR, 2.14; 95% CI, 1.30–3.54; P = 0.003).In a setting of practical care, a PCV prime-PPV boost strategy enhances the frequency, breadth and magnitude of antibody responses against SPP in HIV-infected adults.