Sometimes, more is better.

(See the article by El Sahly et al, on pages 703–12.) Influenza causes significant morbidity and mortality with an estimated 36 000 attributable deaths in the United States annually [1]. Human immunodefi-ciency virus (HIV) infection, specifically , advanced disease (CD4 count ,200 cells/lL), has been associated with excess morbidity and mortality [2]. With the use of combination antiretroviral therapy (cART), hospitalization rates due to influenza among HIV-infected persons declined 10-fold [3]. Although these data highlight the striking beneficial effects of cART, this rate of hospitalization remains similar to that in elderly adults and other high-risk groups. In the current era, respiratory viral pathogens, particularly influenza, cause significant morbidity for HIV-infected individuals [4, 5]. This finding is particularly striking given that one of these studies reported that 76% of the subjects had received annual influenza vaccination [6]. These observations highlight 2 key issues for current HIV care: (1) HIV-infected persons engaged in care are often on cART and more likely to experience usual pathogens rather than classic op-portunistic infections, and (2) despite effective cART, preventative vaccines are not as effective as we would like. Important questions arise: How can we improve the efficacy of preventative vaccines for this immunocompromised population? Will higher antigen dose vaccines yield better protection? For influenza, these questions are particularly relevant given that timely vaccine administration is an important preventive measure in the general population [7]. Unfortunately, current formulations of influenza vaccines are not uniformly protective. Although healthy children and young adults develop sufficient neutralizing antibodies 90% of the time, certain populations at greatest risk for severe influenza (the immuno-compromised, elderly adults, and infants) have significantly lower seroprotection rates after influenza vaccination [8–10]. This variability suggests an underlying inconsistency in the process of generation of immunity across populations and has been previously demonstrated among HIV-infected persons [11]. Nevertheless, a recent meta-analysis demonstrated that influenza vaccine provided a 66% relative risk reduction for the development of influenza illness among HIV-infected individuals [12]. Hence, current guidelines recommend routine vaccination of all HIV-infected persons [13]. Despite clear benefit, how can we improve the immune response in this population? Influenza vaccines induce a T cell–dependent process that leads to the propagation of effective humoral immunity [14]. The depletion of T-helper cells in HIV infection serves as an extreme example of how vaccination can fail because of inadequate T-cell signal-ing. Different strategies can be used to improve the immune response: increasing the …