Influenza vaccines: more options and more opportunities.

Influenza, whether seasonal or pandemic, causes substantial morbidity and mortality. Today, vaccines are the foundation of influenza prevention. Globally, influenza vaccine manufacturing capacity is at an all-time high [1], as are the number and types of influenza vaccines available on the market and in development. In the United States, in addition to the live attenuated and inactivated subunit and split influenza vaccines, a highdose inactivated vaccine for persons aged $65 years, and an intradermally administered inactivated vaccine for persons aged 18–64 years have been recently licensed for seasonal use. This is remarkable progress, considering that as recently as the 2004–2005 influenza season, only one inactivated vaccine was available on the US market [2]. In the United States, all of these vaccines are produced in eggs, although cell-based inactivated and recombinant vaccines are in the late stages of development. Outside the United States, additional inactivated vaccines are licensed for seasonal use, including those manufactured in cell culture, subvirion vaccines combined with the oil-in-water adjuvant MF59 for persons aged $65 years, and whole virus and virosomal vaccines. During the 2009 H1N1 pandemic, many countries, not including the United States, also licensed and used monovalent inactivated vaccines adjuvanted with an oilin-water adjuvant, either AS03 or MF59. When compared with other vaccines, the range of influenza vaccines that are licensed or in development is unprecedented. The robust market and development pipeline are being driven by several factors, including the demand for more seasonal influenza vaccine. Another factor is the desire for faster production and less-expensive alternatives that will make vaccines more widely and equitably available to populations in countries with limited resources, particularly during a pandemic [1]. Additional goals are to improve vaccine performance in high-risk populations, such as the elderly, young children, and the immunocompromised, and to elicit more broadly cross-protective antibodies so vaccines do not require yearly administration. Given the diversity in influenza vaccine formulations, determining the relative benefits of each vaccine is important but extremely challenging. Influenza vaccine performance is influenced by a number of factors, including formulation, age and immune status of the study participants, the vaccine antigen, the match to the circulating strain, and whether the study outcome is immunogenicity or vaccine efficacy. To further complicate the evaluation, the standard measure of influenza vaccine immunogenicity for inactivated vaccines, the hemagglutination inhibition (HAI) assay, exhibits significant variability within and between laboratories. HAI assay results are also affected by the type of vaccine administered and the previous experience of the vaccinee [3]. Thus, it can be extremely difficult to compare the performance of various vaccines between studies. Comparing multiple vaccines within a single clinical trial has the distinct advantage of controlling for the population and strain differences, as well as the assay variability, and offers the best approach for comparing different vaccines. In this issue of the Journal, Ferguson and colleagues compare the immunogenicity and reactogenicity of 1 or 2 doses of a tocopherol-based oil-in-water (AS03) adjuvanted H1N1 monovalent vaccine with 1 or 2 doses of the unadjuvanted vaccine [4]. For the reasons given above, the multiple-group comparisons possible within this single study are a strength. The results support previous observations that inactivated influenza vaccines are more immunogenic in younger adults than in older adults, in individuals previously seropositive to the vaccine antigen at baseline, and in recipients of the adjuvanted vaccines. As shown in this article, the 3.75-lg dose of adjuvanted vaccine was superior to 3.75 mg of unadjuvanted vaccine after a single dose in younger and older adults. Likewise, the lower doses of adjuvanted vaccines were noninferior to higher doses of the unadjuvanted vaccine, confirming the dose-sparing aspects of adjuvants [4, 5]. These dose-sparing effects are particularly Received 14 August 2011; accepted 15 August 2011. Correspondence: Kathleen M. Neuzil, MD, MPH, Vaccine Development Global Program, PATH, 1455 NW Leary Way, Seattle, WA 98108 ([email protected]). The Journal of Infectious Diseases 2012;205:700–1 The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected] DOI: 10.1093/infdis/jir646