Maraviroc does not affect humoral response to the pandemic influenza A-H1N1v 2009 adjuvanted vaccine in HIV-1-infected patients
Canestri, Anaa,c; Krivine, Anneb; Assoumou, Lambertc; Le Corre, Moniqued; Rozenberg, Floreb; Marcelin, Anne-Genevièvec,e,f; Schneider, Luminitaa,c; Samri, Assiad; Carcelain, Guislainea,e,g; Autran, Brigittea,e,g; Katlama, Christinea,c,e; Guihot, Améliea,e,g
aAP-HP, Hôpital Pitié-Salpêtrière, Maladies Infectieuses et Tropicales, France
bAP-HP, Hôpital Saint Vincent Paul, Laboratoire de Virologie, France
cINSERM, UMR 943, France
dINSERM, UMR S945, France
eUniversité Pierre et Marie Curie- Paris 6, France
fAP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, France
gAP-HP, Hôpital Pitié Salpêtrière, Laboratoire d'Immunologie cellulaire et tissulaire, Paris, France.
Received 2 August, 2010
Revised 1 September, 2010
Accepted 2 September, 2010
Correspondence to Dr Ana Canestri, Service des Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, 47 bd de l'Hôpital, 75013 Paris, France. Tel: +33 1 42 16 01 03; fax: +33 1 42 16 01 65; e-mail: firstname.lastname@example.org
Immune changes induced by the CCR5 antagonist maraviroc raise the question of an impairment of responses to vaccines. We evaluated the immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009 vaccine in HIV-1-infected patients with suppressed HIV viremia with or without a maraviroc-containing regimen. Seroprotection, seroconversion, and geometric mean titer ratio of specific antibody titers did not differ between groups. These results suggest that maraviroc does not significantly affect the immune response to this adjuvanted vaccine.
Maraviroc (MVC) blocks HIV-1 entry into the CD4 host cells  by binding to the chemokine receptor CCR5. Several studies have shown an increased severity of West Nile virus infection and tick-borne encephalitis virus in patients with the CCR5Δ32 deletion [2,3], suggesting a key role of CCR5 in immune control of viruses. In mice, a CCR5 gene deletion is associated with a more severe influenza infection . Because CD4+CCR5+ T cells of memory phenotype help with differentiation of B cells into antibody producing plasma cells and help CD8 antiviral effector T cells, MVC may influence immune response to live or attenuated viruses. These observations led some authors to recommend avoiding yellow fever vaccination in HIV-1-infected patients treated with MVC . However, the MVC immunomodulatory effects on responses to vaccines remain unknown. Although one dose of the 2009 pandemic influenza A-H1N1v adjuvanted vaccine had been shown to trigger a protective antibody response to influenza in HIV-1 patients , concerns were raised about a possible interference of MVC treatment with responses to this highly immunogenic vaccine.
To test such hypothesis, we conducted a prospective case–control study to compare the humoral immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009 vaccine. HIV-1 patients on combined antiretroviral therapy (cART) containing MVC (MVC group) or not (control group) were studied after providing informed consent according to ethical recommendations.
All patients had to be on cART with a viral load less than 50 copies/ml. Control patients were matched for sex, age (±5 years), and CD4 cell counts (±75 cells/μl). All patients received one dose (3.75 μg hemagglutinin) of the 2009 Pandemrix influenza A-H1N1v adjuvanted vaccine at day 0 (D0) between 23 November 2009 and 4 January 2010. Influenza-specific antibody titers were measured at D0 and D21 by using a hemagglutination inhibition assay (HIA) modified from Kendal and Skehel  by the use of human O Rh- red blood cells and the nonadjuvanted influenza A-H1N1v 2009 vaccine Panenza as antigen. Immunogenicity was evaluated upon percentages of seroprotection (antibody titers ≥1/40), seroconversion (antibody titers <1/10 to ≥1/40) or four-fold increase in antibody titers, and geometric mean titer (GMT) ratio (D21/D0). Any clinical events, changes in CD4 cell counts, and HIV viral load were recorded.
We included 22 patients in the MVC group and 29 in the control group. Baseline characteristics were similar between both groups and showed a vast majority of men (86 and 93%), a median (min–max) age of 50 (40–74) and 53 (37–78) years, and a median CD4 cell count of 459/μl (41–1002) and 520/μl (115–1065) in the MVC and the control groups, respectively. Patients had been infected for a median duration of 20 (9–25) and 15 (2–25) years, with a nadir of CD4 cell count of 70/μl (3–274) and 109/μl (1–571) in the MVC and control groups, respectively. Only nine of 22 (41%) patients in the MVC group and 11 of 29 (38%) in the control group had previously received the seasonal 2009/2010 influenza vaccine (P = 1.00) with a median delay of 40 (21–79) days before the pandemic vaccine. Five patients in each group experienced side effects: three patients in the MVC group and five in the control group experienced systemic reactions (fever and fatigue). Two patients in the MVC group and three in the control group complained for a local reaction (pain and redness). Median CD4 cell count changes between D21 and D0 were +11/μl (−248–107) in the MVC group and −12/μl (−282–591) in the control group. All patients remained aviremic with a viral load less than 50 copies/ml at D21 except for two patients who experienced a blip at week 4 that was subsequently suppressed.
Influenza immunogenicity analysis showed seroprotection at D0 in four of 51 patients (two in the MVC and two in the control group, Fig. 1a). Patients who received the seasonal influenza vaccine before the pandemic one had a higher baseline antibody GMT for influenza A-H1N1v virus than nonseasonal vaccinated patients: 17.72 (13.05–24.07) vs. 8.42 (4.84–10.87), respectively (P < 0.001). After vaccination, seroprotection was obtained at D21 for 20 of 22 (91%) patients in the MVC group and 27 of 29 (93%) in the control group (P = 1.00; Fig. 1b). Seroconversion was observed at D21 in 17 of 22 patients (77%) in the MVC group and 25 of 29 (86%) in the control group (P = 0.47; Fig. 1c). The GMT ratios (D21/D0) were 8.3 [95% confidence interval (CI) 5.3–13] for the MVC group and 11.6 (95% CI 7.4–18.2) for the control group (P = 0.35; Fig. 1d). The prior seasonal influenza vaccine did not influence the GMT at D21: 113.2 (72.6–176.5) vs. 113.8 (83.8–154.5), respectively (P = 0.53). Neither the duration of HIV infection nor the CD4 nadir or the CD4 cell counts at D0 were associated to the antibody response to the pandemic vaccine. Finally, the duration of exposure to MVC did not significantly influence the response to this adjuvanted vaccine.
Our study showed that MVC did not significantly affect the antibody response to the influenza A-H1N1v adjuvanted vaccine in HIV-1-infected patients despite a slightly lower antibody levels in patients receiving MVC. In addition, this influenza A-H1N1v adjuvanted vaccine showed a good immunogenicity and a good tolerance in HIV-1 patients, with a persisting undetectable viral load while on cART. Noteworthy, the seasonal influenza vaccine may have conferred some protection to the pandemic A-H1N1v virus, suggesting a cross-reactivity between the pandemic A-H1N1v and the A-H1N1/Brisbane/59/07 strain contained in the seasonal vaccine.
Equation (Uncited)Image Tools
Altogether these results, observed, however, in a small series of patients, suggest that the MVC CCR5 antagonist does not impair the response to influenza vaccines in stably suppressed HIV-1-infected patients with subnormal CD4 cell counts. It remains to be determined whether such a lack of negative immunomodulatory effect of CCR5 antagonists reflects the strong immunogenicity of this adjuvanted vaccine or can be extrapolated to any vaccine preparation.
Equation (Uncited)Image Tools
The authors want to thank the Institut de Microbiologie et Maladies Infectieuses for his organizational support.
A.C., C.K., G.C., B.A., and A.G. designed the study and wrote the article. A.C. and L.S. selected patients. M.L.C. and A.S. organized reception of blood samples. A.K. and F.R. performed HIA analysis. A.G.M. performed virological studies. L.A. performed statistical analysis. L.A. and M.L.C. contributed equally to this study.
The present work will be presented to the AIDS Vaccine 2010 International Conference in Atlanta, Georgia (abstract #188141).
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