The study design allowed the impact of the PPV boost in patients from the prime-boost group to be evaluated. For this, we compared frequency and distribution of responders (i.e., patients who experienced both a twofold increase in SPP-specific antibody levels and IgG concentrations > 1 μg/ml), 4 weeks following the administration of either the PCV in the prime-boost group or PPV in the PPV group. The distribution of frequency of responders in the categories 0, 1–2, 3–4 and 5–7 SPP were 9, 20, 22 and 49% in the prime-boost group at week 4 and did not differ significantly from frequency of responders of the PPV-alone strategy at week 8: proportional OR 1.36 (95% CI, 0.82–2.25; P = 0.23). Altogether, these results showed that the PPV boost in patients from the prime-boost group contributed to increase the rate of responders at week 8, as compared to a single PPV administration in patients from the PPV group.
At week 8, compared with the PPV group, SPP-specific IgG concentrations (geometric mean of antibody concentrations) were significantly higher in patients who received the PCV prime followed by the PPV boost for six of seven serotypes shared by the PCV and PPV vaccines: serotypes 4, 9V, 14, 18C, 19F, and 23F. As expected, there were no differences between groups in the IgG antibody concentrations for serotypes 5 and 1 which are not contained in the PCV, indicating that PCV prime did not inhibit any of the PPV unshared subtype responses (Table 2).
The sustainability of SPP-specific IgG responses was evaluated at week 24. Patients from the prime-boost group had significantly higher levels as compared to the PPV-alone group for four of seven SPP shared by the two vaccines (Table 2). The frequency and the distribution of patients who experienced both a twofold increase in SPP levels and IgG concentrations > 1 μg/ml was significantly higher in the prime-boost group as compared with the PPV-alone group. Responders to 0, 1–2, 3–4 and 5–7 SPP were 17, 30, 24 and 30% in the prime-boost group as compared to 23, 40, 27 and 10% in the PPV group: proportional OR, 2.14 (95% CI, 1.30–3.53; P = 0.003) (Fig. 3).
Finally, we analyzed predictive factors of IgG-specific immunological responses to vaccination. In the multivariate model (Table 3), the prime-boost strategy remained significantly associated with a better immunological response. Moreover, smokers and patients co-infected with HCV had a significantly lower chance of being responders to vaccination than others. However, in these categories of patients, the rate of responders remained higher in those who received the prime-boost regimen as compared to recipients of the PPV-alone.
In this randomized, controlled trial, we show that a vaccination combining PCV as a prime followed by a PPV boost led to a higher rate of immunological responders as compared to the administration of a single injection of the currently recommended PPV. Moreover, the prime-boost strategy led to a higher level of SPP-specific IgG against all but one, of the seven polysaccharides shared by the two vaccines. Both vaccine strategies were well tolerated.
Studies evaluating antibody responses to PPV consistently concluded low immunogenicity and lack of efficacy in HIV-infected patients with CD4 cell counts < 500/μl [17,23,24,27–29,41]. Several trials performed in children, who have poor responses to PPV, have shown that the PCV is highly efficacious against invasive disease [34,35,42,43]. Therefore, conjugated vaccines might be a very promising strategy to protect high-risk adults. For example, vaccination of adult HIV-infected patients with conjugated-Hemophilus influenzae b (Hib) vaccine led to a greater antibody response than the Hib polysaccharide vaccine . However, regarding pneumococcal vaccination, results are less clear-cut since no differences in immunological responses elicited by a single dose of PCV compared to PPV were shown in adult patients with CD4 cell counts > 200/μl . This defect in humoral immunity was not overcome by revaccination either by a double dose of PPV [31,32] or by vaccination with one or two doses of PCV [29,41].
As seven SPP are shared by the PPV and PCV, we evaluated whether a prime with PCV would be more effective in obtaining a longer-term response to a boost with PPV. We chose this combination following the demonstration of a booster effect of the PPV after priming with PCV both in HIV and non-HIV infected infants and children [45–47]. Moreover, we hypothesized that this strategy might help to extend the breadth of the antibody response against SPP serotypes. Our design allowed evaluation of the rate of responders to the seven SPP shared by the two vaccines and to SPP 1 and 5 contained only in the PPV. Following administration of the PPV boost in patients primed with PCV, the proportion of responders to 5–7 SPP became 20% higher as compared to the PPV group. Our results contrast with those of another study showing no additional increases in antibody concentrations elicited by a dose of PPV following a first dose of PCV in HIV-infected patients with CD4 cell counts > 200 cells/μl . Several differences between this study and our results may explain these different findings including the timing of the PPV boost 8 weeks following the PCV, the small sample size (18 patients received the combination strategy) and the high rate of lost of follow-up (20%) which jeopardized the power of this study.
Continued uncertainty regarding the nature of SPP vaccine responses that translate into vaccine efficacy in the setting of HIV infection underscores the need to define useful surrogates for vaccine efficacy. The levels of IgG required for protection remain unknown. However, previous studies have shown that vaccine failures are often associated with lack of antibody response [49–51]. We used two different criteria of antibody responses. The first one (twofold increase in IgG levels) has been routinely used in studies of pneumococcal immunization in adults [23,26,48]. However, it does not assess the absolute post-vaccination value which could be a surrogate marker of protection against invasive pneumococcal disease. To overcome this, we used a second and stricter criterion of response which includes both a twofold response and a level of antibody ≥ 1 μg/ml. Our results show that the prime-boost strategy led to higher values of the geometric mean of IgG-specific for six of the seven serotypes shared by the two vaccines, except for SPP 6b, which is known to be an antigen with poor immunogenicity [52,53]. It seems unlikely that the low antibody responses against serotype 6b could have any clinical relevance, because this serotype is rarely found in adults with pneumococcal invasive disease .
Several studies reported that immunological responses to vaccination with either T-cell-dependent antigens or SPP are impaired in HIV-infected adults with low CD4+ cell count [55,56]. In the context of the multiple immune dysregulations that complicate HIV infection, SPP specific suboptimal antibody responses may be less protective. Our results show that a combination strategy including a prime with a T-cell dependent antigen may help to overcome limitations to an effective antibody response in HIV infection. These provide arguments for testing such strategy in patients who less likely may have chance to mount a significant antibody response to SPP such as non-white patients or individuals with low CD4+ cell counts .
Interestingly, we observed that a higher rate of responders was maintained 6 months following vaccination with PCV combined with PPV. This observation might have clinical relevance since a rapid loss of vaccine antibodies is observed in HIV individuals receiving either PCV or PPV-alone . The limited responses after re-immunization of patients with the current PPV do not overcome this loss of antibody titres and reinforce the need for a more immunogenic strategy. As with previous studies, we found that the percentages of responders to SPP dropped in each group of the study six months following the end of the vaccination. Previous studies have shown that the rate of decline of vaccine antibodies against SPP is similar in HIV-infected individuals and healthy controls suggesting that the period of protection following vaccination is dependent on the levels achieved after vaccination [32,41,57]. We found that the levels of IgG specific to four of seven of the SPP shared by the two vaccines remained significantly higher in recipients of the PCV-PPV combination as compared to patients vaccinated with PPV alone. This observation suggests that the period of protection might be significantly prolonged in patients who received a sequential vaccination with PCV and PPV.
We evaluated the impact of the prime-boost strategy in a multicentric trial as close as possible to the practical care of a population of HIV-infected individuals. Although a vast majority of patients were treated with HAART, all patients treated or not with antiviral drugs were eligible to participate to this study. Similarly, there was no restriction based upon the nadir CD4 T cell count, a clear predictive factor of the response to vaccination in HIV-infected patients [18,19,41,55]. We found that the efficacy of the prime-boost strategy remained significantly higher than that of PPV alone when adjusted for CD4 cell counts, viral load and antiviral therapy. In the multivariate analysis, the prime-boost strategy remained associated with better immunological responses in smokers and patients with HCV infection. Several studies have shown that cirrhosis is a risk factor for both pneumococcal infection and low response to vaccination against SPP [58–60]. In addition, HCV infection was found to inhibit humoral response to hepatitis B virus vaccine in patients . More recently, HCV infection was identified as a risk factor for invasive pneumococcal disease in HIV-infected patients . However, to our knowledge, an association between HCV infection status and response to pneumococcal vaccination in HIV-infected patients has not been documented previously. This result would help to identify, among HIV-infected individuals, subjects who likely may have a better benefit of the prime-boost strategy.
Our study provides evidence to support the use of a PCV primed-PPV boosted strategy to overcome limitations of the immunogenicity of the currently recommended immunization with PPV alone. We found that this strategy led to a higher efficacy of the vaccination in frequency, breadth, magnitude and sustainability of antibody responses among HIV-infected adults with CD4 cell counts between 200 and 500 cells/μl.
We would like to thank Dr Bernard Fritzell (Wyeth Pharmaceuticals Vaccines) for his contribution to this paper, Dr Madore DV (Wyeth-Lederlé Rochester, USA) for the evaluation of IgG responses to pneumococcal serotypes, Pr David Goldblatt (Immunobiology Unit, Institute of Child Health, UK) for expertise in the quality control evaluation of IgG responses, and Mrs Inga Tschöpe for checking the results of statistical analysis. We also gratefully acknowledge the contribution of the Data and Safety Monitoring Committee: France Mentré, Philippe Morlat. This study was performed with the financial support of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS).
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Appendix: Members of the ANRS 114-Pneumovac Study Group
P. Lesprit,Y. Levy (principal investigators); G. Chêne (trial coordinator); N. Sarrazin (trial monitor); G. Pedrono (trial statistician); C. Rabian (trial immunologist); P. Bursachi, M.-J. Commoy, J.-F. Delfraissy, F. Denis, B. Fritzell, C. Goujard, R. Salamon, R. Tubiana, J. P. Viard.
Participating clinical departments and investigators
Hôpital Avicenne, Bobigny: A. Krivitzky, M. Bentata, S. Makki, R. Mansouri, L. Guillevin, B. Jarousse, A.-K. Klutse, G. Obenga, P. Honoré-Berlureau, Y. Baazia and S. Soreda; Hôpital Saint-Louis, Paris: J.-P. Clauvel, E. Oksenhendler, L. Gerard, J. Delgado, J.-M. Molina, N. Colin de Verdière, P. Palmer, I. Madelaine; Hôpital Pellegrin, Bordeaux: M. Dupon, J.-M. Ragnaud, D. Neau, I. Raymond, I. Garrigue, J.-P. Dupin; Hôpital Necker, Paris: Ch. Boitard, J.-P. Viard, S. El Marsafy, R. Lahoulou, A. Mogenet, C. Broissand; Hôpital de Bicêtre, Le Kremlin-Bicêtre: J.-F.Delfraissy, C. Goujard, D. Pereti, Y. Quertainmont, P. Robquin, O. Segeral, S. Poirier, M.-T Rannou, N. Idri, C. Le Tiec; Hôpital Cochin, Paris: D. Sicard, D. Salmon, O. Launay, B. Silbermann, C. Desaint, A. Krivine, C. Guérin; Hôpital Henri-Mondor, Créteil: A. Sobel, Y. Lévy, P. Lesprit, A.-S. Lascaux, Ch. Chesnel, C. Jung, A. Miladi, C. Antoine; Hôpital Pitié-Salpêtrière, Paris: F. Bricaire, Ch. Katlama, I. Boubezari, S. Pierre-François, L. Schneider, C. Seulié, M.-H. Fievet; Hôpital Saint-Antoine, Paris: P.-M. Girard, A.-M. Béglé, F. Besse, R. Mouchotte, A. Charrois, A. Duaguenel-Nguyen; Hôpital Bichat, Paris: P. Yeni, I. Fournier, S. Lariven, B. Phung, P. Ralaïmazava, Ch. Gaudebout, J. Gerbe, D. Descamps, S. LePoole; Hôpital Gui de Chauliac, Montpellier: J. Reynes, P. André, V. Baillat, V. Le Moing, C. Merle, M. Vidal, J.-M. Fondère, I. Roch-Torreilles; Hôpital Hôtel-Dieu, Nantes: F. Raffi, P. Morineau, C. Allavena, B. Bonnet, H. Hue, E. Guarnier, A. Lepelletier; Hôpital Les Oudairies, La Roche sur Yon: P. Perré, O. Aubry, S. Leautez, C. Leroy, I. Suaud, A.-S. Poirier, A. Lepelletier; Hôpital de L'Archet, Nice: P. Dellamonica, V. Rahelinirina, M.-A. Sereni, S. Benhamou, M.-Ch. Rigault; Hôpital Purpan, Toulouse: P. Massip, B. Marchou, M. Alvarez, E. Bonnet, L. Cuzin, M. Obadia, F. Balsarin, M. Barone, M. Heraud, I. Peyranne.
Data and safety monitoring board
F. Mentré, P. Morlat.
Coordinating trial centre
INSERM U593, Bordeaux, France (G. Chêne, N. Sarrazin, G. Pedrono, I. Tschöpe, G. Palmer)