In a univariate and multivariate analysis, the predictors of persistence of haemagglutination inhibition titers of 1 : 40 or greater at months 6 and 12 were the AS03A-adjuvanted H1N1v vaccine [odds ratio (OR) = 3.8, P = 0.00001 at month 6; OR = 2.7, P = 0.0002 at month 12), HAART (OR = 2.0, P = 0.028 at month 6; OR = 1.7, P = 0.15 at month 12) and current smoking (OR = 0.55, P = 0.04 at month 6; OR = 0.57, P = 0.03 at month 12) (details are presented under Supplemental Digital Content, http://links.lww.com/QAD/A259). Seasonal 2010 influenza vaccination was independently associated with haemagglutination inhibition titers of 1 : 40 or greater at day 364 (OR = 5.6, P = 0.026).
Microneutralization results were overall comparable to haemagglutination inhibition results. However, the microneutralization antibody titers were slightly lower than haemagglutination inhibition titers as well as seroconversion rates (Table 1, Fig. 1).
In this randomized trial designed to evaluate the immunogenicity and the safety of 2009 A/H1N1v vaccine, adjuvanted or not with AS03A, in a population of HIV-1-infected adults, we observed that two doses of the adjuvanted vaccine formulated with 3.75 μg of haemagglutinin antigen confers a higher long-term immune response than two doses of the nonadjuvanted vaccine.
The results of Crum-Cianflone et al. showed that a single dose of monovalent 2009 influenza A/H1N1v nonadjuvanted vaccine did not generate durable seroprotective antibody response in HIV-1-infected patients. Only 43% of them had a postvaccination titer at least 1 : 40 at month 6 vs. 73% in healthy adults. In the general population, with a trivalent seasonal vaccine including one H1N1 strain, seroprotection rates were maintained above European criteria at 6 months and decreased to 42–52% after 1 year in adults less than 65 years . Our results suggest that a second dose of nonadjuvanted vaccine in HIV-1-infected patients could improve long-term seroprotection up to 59.4% at month 6. One year after vaccination, 43.3% of them had seroprotective levels. This suggests that vaccination with two doses of nonadjuvanted H1N1v vaccine in HIV-1-patients with controlled virologic parameters allows achieving comparable long-term seroprotection rates as one dose in the general population.
By comparison, with two doses of adjuvanted vaccine, seroprotection levels as high as 83.7% (89.9% in patients with HAART) were achieved at month 6. However, recent results showed higher seroprotection rate as high as 96.6% in healthy adults receiving two doses of adjuvanted vaccine . One year after vaccination, seroprotection rates in our study remained high at 70.4% (75.0% in patients with HAART). Better seroprotection rates were obtained in patients with HAART as reported previously in case of seasonal influenza vaccination . Our study demonstrates that this benefit is observed up to 1 year after 2009 A/H1N1v vaccination.
Neutralizing antibody responses were also observed in both groups after vaccination. Although the overall kinetics of the neutralizing antibody response paralleled that of the haemagglutination inhibition response, lower GMTs and seroconversion rates were observed 6 and 12 months postvaccination. Such variation may partly correspond to different biological activities of the antibodies measured by the two methodologies. However, neutralizing seroconversion rates observed in healthy adults receiving two doses of adjuvanted vaccine were as high as 76% at month 6 as compared to 43.2% (54.3% in patients with HAART) in our study .
Influenza vaccination has been shown to cause transient increases in plasma HIV-1 RNA levels. In a Swiss study, this was observed in previously aviraemic patients after two doses of the AS03A-adjuvanted H1N1v vaccine . A subsequent nonadjuvanted dose of a trivalent split-virus influenza vaccine, containing the 2009/A/H1N1v strain did not reproduce this finding when administered 1 year after AS03A-adjuvanted H1N1v vaccination, and, therefore, the authors concluded on a nonantigen-specific adjuvant effect. Although our study was not designed to precisely evaluate this outcome, no significant impact on HIV-1 RNA or CD4 levels were found, whatever the vaccine used.
Our study has some limitations. The present results were based on accepted immunological surrogates but other components of the immune response have not yet been explored. T-cell-mediated immune response is known to play a critical role in host defense against influenza virus infection. Therefore, assuming protection only on the basis of humoral response could be questioned, particularly in immunosuppressed patients. The results of a recent seasonal influenza vaccination trial done in Africa in HIV-1-infected patients suggested that the likely benefit of influenza immunization was underestimated when relying only on humoral immunogenicity markers .
In conclusion, our long-term results in HIV-1-infected patients demonstrate that two doses of nonadjuvanted vaccine in HIV patients achieve long-term seroprotection rates comparable to the general population after a single dose. Administration of two doses of adjuvanted influenza vaccine maintains higher seroprotection titers up to 1 year after vaccination than two doses of nonadjuvanted vaccine, however, lower than in the general population.
We thank the study participants and the participating clinicians at each site, the ‘French Research Program on Pandemic H1N1v Flu: Institut de Microbiologie et Maladies Infectieuses’, Francis Beauvais for his help in preparing the manuscript; GSK Biologicals staff (Jeanne-Marie Devaster, F.R., Laurence Baufays, Nathalie Clyti, Sophie Muller, Marie-Hélène Chautard, and Isabelle Naeije for support in study management, Karl Walravens, Urban Lundberg, and Roger Bernhard for serological testing, and Géraldine Drevon for manuscript review). Trial registration: Clinicaltrials.gov identifier: NCT01008813.
O.L. and J.P.A., C.Desaint and C.Durier prepared the first draft of the manuscript. All authors contributed to the content of the manuscript (including the author employed by GSK Biologicals) and to the design and conduct of the study; the analysis and interpretation of the data; and the preparation of the manuscript. C. Durier performed statistical analysis. O.L. had final responsibility for the decision to submit the manuscript for publication.
ANRS 151 HIFLUVAC study group members: G. Pialoux, L. Slama (Hôpital Tenon, Paris), J.F.D., J. Ghosn, M.T. Rannou, E. Fourn, Y. Quertainmont (Hôpital de Bicêtre, Le Kremlin-Bicêtre), F. Raffi, C. Allavena, C. Biron, D. Besson, H. Hue (Hôpital de l’Hôtel-Dieu, Nantes), J. Reynes, J.M. Jacquet (Hôpital Gui de Chauliac, Montpellier), J.M. Molina, N. Colin de Verdière (Hôpital Saint-Louis, Paris), P.M.G., M.C. Meyohas, D. Bollens (Hôpital Saint-Antoine, Paris), P. Yéni, X. Duval, B. Phung, C. Godard, N. El Alami albi (Hôpital Bichat-Claude Bernard, Paris), O.L., P. Loulergue, L. Belarbi, L. Iordache (Hôpital Cochin, Paris), A. Sobel, Y.L., E. Bamago, S. Doninguez, C. Dumont, C. Chesnel (Hôpital Henri Mondor, Créteil), H. Laurichesse, J. Beytout, C. Jacomet, (Hôpital Gabriel Montpied, Clermont Ferrand), D. Rey, J.M. Lang, P. Fischer, M. Partisani (Hôpitaux Universitaires, Strasbourg), Y. Yazdanpanah, F. Ajana, T. Huleux (Hôpital Gustave Dron, Tourcoing), F.L., C. Delafontaine, C. Guglielminotti, A. Frésard, P. Fouilloux, V. Ronat (Hôpital Bellevue, Saint-Etienne), T.M., S. Wassoumbou (Hôpital de Brabois, Vandoeuvre-lès-Nancy), J-F. Bergmann, A.R., M. Parrinello (Hôpital Lariboisière, Paris), C.M., F. Fily, M. Ratajczak (Hôpital Pontchaillou, Rennes), F. Bricaire, C. Katlama, A. Chermak (Hôpital Pitié-Salpêtrière, Paris), P. Dellamonica, A. Leplatois (Hôpital de l’Archet, Nice), J. Saillard, S. Couffin-Cadiergues, A. Bouxin-Métro (ANRS, Paris), J.P.A., C. Desaint, V. Foubert, M. Resch, A. Grenier, M. Le Cornec, E. Moreau, S. Marie-Antoine, Y. Saïdi, A. Arulananthan, C. Durier (Methodology and coordinating center, INSERM SC10, Villejuif France).
REIVAC Network: O.L. (coordinator: CIC BT505, Paris), F.L. (CIC CIE3 axe vaccinologie, Saint Etienne), X. Duval (CIC P-007, Bichat-Claude Bernard, Paris), N. Colin de Verdière (Service de maladies infectieueses et tropicales de Saint-Louis, Paris), H. Laurichesse, J. Beytout (CIC P-501, Clermont Ferrand).
Scientific committee: O.L., coordinator (Université Paris Descartes, Hôpital Cochin, Inserm, Paris); J.P.A., C. Durier, C. Desaint (Inserm SC10, Villejuif); Pierre Loulergue (Hôpital Cochin, Paris); Xavier Duval (Hôpital Bichat, Paris); Christine Jacomet (CHU Clermont Ferrand, Clermont Ferrand); Constance Delaugerre (Hôpital Saint-Louis, Paris); Sylvie van der Werf (Institut Pasteur, Paris); Sophie.Muller (GSK, Paris); F.L. (Hôpital Bellevue, Saint-Etienne), Jade Gohsn, J.F.D. (Hôpital de Bicêtre, Kremlin-Bicêtre), Marianne Lhenaff (TRT5, Paris), Juliette Saillard, Sandrine Couffin-Cadiergues (ANRS, Paris).
This study was sponsored and funded by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, Paris, France). The sponsor of this study did not impose any impediment on the publication of the study's results.
GSK Biologicals provided the vaccines and performed immunological tests.
Conflicts of interest
O.L. has been an investigator on vaccine studies sponsored by GlaxoSmithKline Biologicals and other companies and received travel support to attend scientific meetings from GlaxoSmithKline and other companies. F.R. is an employee of GSK Biologicals and has shares from GSK Biologicals. C.D., C.D., F.L., P.M.G., Y.L., T.M., C.M., A.R., C.K., A.G., J.F.D., J.P.A. have no conflicts of interest.
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adjuvant; flu vaccine; HIV; immunogenicity; persistence
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