Long-term Immune Responses to Vaccination in HIV-Infected Patients: A Systematic Review and Meta-Analysis

HIV/AIDS INVITED ARTICLE Kenneth H. Mayer, Section Editor Long-term Immune Responses to Vaccination in HIV-Infected Patients: A Systematic Review and Meta-Analysis Solen Kernéis,1,2,3,4,5 Odile Launay,1,2,4 Clément Turbelin,3,5 Frédéric Batteux,1,6 Thomas Hanslik,7,8 and Pierre-Yves Boëlle3,5 1 Paris Descartes University, 2Centre d’Investigation Clinique (CIC) BT505 and 3Unité Mixte de Recherche en Santé (UMR S) 707, Inserm, 4CIC BT505, Assistance Publique-Hôpitaux de Paris, 5UMR S 707, Pierre et Marie Curie University, 6Laboratoire d’Immunologie Biologique, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris; 7Department of Internal Medecine, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt; and 8Versailles Saint-Quentin-en-Yvelines University, Versailles, France Vaccine-induced antibodies may wane more quickly in persons living with human immunodeficiency virus (HIV) than in healthy individuals. We reviewed the literature on vaccines routinely recommended in HIVinfected patients to estimate how seroprotection decreases over time in those who initially responded to immunization. For each study retrieved from the literature, the decrease of seroprotection was modeled with a log binomial generalized linear model, and data were pooled in a meta-analysis to provide estimates of seroprotection 2 and 5 years after the last vaccine administration. Our analyses confirmed that the duration of seroprotection was shorter in HIV-infected patients and that with current guidelines, a substantial proportion of patients would have lost protective antibodies before a booster was proposed. We therefore discuss the implications for the monitoring of antibody levels and timing of revaccination in these patients. Keywords. vaccination; HIV; meta-analysis. Immune responses to most vaccines are known to be impaired in patients with human immunodeficiency virus (HIV) infection [1, 2]. However, besides the primary response, long-term persistence of protection has been poorly documented. As of today, recommendations on the timing of booster injections were based on data collected in healthy persons, although antibody decay patterns may be different. In this respect, an important step is to estimate how seroprotection decreases over time among patients who initially responded to immunization. In the current study, we reviewed data on long-term persistence of antibody concentrations after vaccination in HIV-infected patients. There were Received 5 November 2013; accepted 14 December 2013; electronically published 10 January 2014. Correspondence: Solen Kernéis, MD, PhD, CIC de Vaccinologie Cochin Pasteur, Hôpital Cochin, 27 Rue du Faubourg Saint Jacques, 75679 Paris Cedex 14, France (). Clinical Infectious Diseases 2014;58(8):1130–9 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: . DOI: 10.1093/cid/cit937 1130 • CID 2014:58 (15 April) • HIV/AIDS 3 main reasons for this choice: (1) antibody concentrations are reported in most vaccine trials, providing enough data to allow meta-analysis; (2) correlates of protections have been defined for most vaccines; and (3) antibody levels for most antigens can be routinely assessed with standardized methods. For some vaccines (ie, measles, varicella, and yellow fever), cell-mediated immunity is the critical determinant of protection; however, methods for evaluating cellular responses are not easily comparable between studies, and correlates of protection not yet established. Our goal here was to provide a summary of available data to guide recommendations on revaccination in HIV-infected persons. METHODS Search Strategy and Selection Criteria Using PubMed, we searched the MEDLINE database for English-language articles up to January 2013, without date restriction, using the terms vaccine, antibodies, follow-up, long-term, decline, duration, and HIV (see search equation in the Supplementary material). The review and meta-analysis were conducted according to the PRISMA guidelines. Studies were selected by 1 author (S. K.) according to the eligibility criteria: original experimental or observational studies on licensed vaccines in patients living with HIV, reporting measurements of antibody titers beyond 6 months after the last vaccine dose administration. Reports on influenza vaccines were excluded. The reference lists of all relevant articles were examined for additional data sources. For each article, we abstracted the study design, vaccination protocols, sample size, follow-up duration and the percentage of “primary responders” ( patients who had mounted protective antibody titers after immunization) who remained seroprotected over time. Protective levels defining seroprotection were those reported by the authors and are detailed in the Supplementary Information. Where relevant, the percentages of seroprotected patients were pooled in a meta-analysis. The meta-analysis was restricted to prospective studies and to vaccine antigens for which ≥2 studies were available. No metaanalysis was undertaken for pneumococcal vaccines because the specific antibody levels necessary for adequate protection against pneumococcal disease are not clearly defined, even in healthy persons [3]. Data Analysis To account for the great heterogeneity in follow-up times between the different studies, we first modeled for each study the decrease in seroprotection P(t), as a function of time since immunization, as P(t) = exp(-β.t), where exp(−β) was the relative decrease in protection per additional time unit (t) since immunization. Data were fit using log binomial generalized linear models. The predicted percentages of seroprotected individuals 2 and 5 years after immunization in each study were then pooled in a meta-analysis with random effects and presented in forest plots. All analyses were made using R software, version 2.13.2 (R Development Core Team, R Foundation for Statistical Computing; http://www.r-project.org). RESULTS Of the 159 potentially relevant studies, 54 were selected for the qualitative review (Figure 1). For each vaccine, percentages of seroprotection retrieved from the literature are presented in Figure 2. Median follow-up ranged from 9 months to 9 years after the last vaccine dose. The median number of patients per study was 40 (interquartile range, 18–63). Data were available for 13 vaccine antigens: Streptococcus pneumoniae (n = 14), hepatitis B (n = 12), measles (n = 12), hepatitis A (n = 5), tetanus (n = 8), yellow fever (n = 3), Haemophilus influenzae type b (n = 3), rubella (n = 2), varicella, (n = 1), pertussis (n = 1), poliovirus (n = 1), mumps (n = 1), and Japanese encephalitis (n = 1). Of the 54 studies included in the review, 19 fit the eligibility criteria for meta-analysis. Others were excluded because they were studies of pneumococcal vaccine (n = 14), were retrospective (n = 13), did (...truncated)