Ekiert D. report progress toward the goal of an influenza virus vaccine which would protect against multiple strains. Our approach is based on presentation to the host immune system of a region of the influenza viruscalled a headless hemagglutinin (headless HA)which is similar among a multitude of diverse strains. We show that vaccination of mice with a headless HA confers protection to these animals against a lethal influenza virus challenge, thereby demonstrating the viability of the approach. Through further development and testing, we predict that a single immunization with a headless HA vaccine will offer effective protection through several influenza epidemics. INTRODUCTION Influenza in humans is a respiratory disease that ranges in severity from subclinical infection to primary viral pneumonia, which can result in death. The clinical effects of infection vary with the virulence of the influenza strain and the exposure history, age, and immune status of the host. The cumulative morbidity and mortality caused by seasonal influenza are substantial due to the relatively high attack rate: in the United States, influenza viruses infect an estimated 10% to 15% of the population (1, 2) and are associated with approximately 30,000 deaths each year (3, 4). In addition to causing annual epidemics, influenza viruses are the cause of infrequent pandemics. Due to the lack of preformed immunity against the major viral Biricodar dicitrate (VX-710 dicitrate) antigen (hemagglutinin [HA]), pandemic influenza can affect more than 50% of the population in a single year and often causes more severe disease than epidemic influenza. A stark example is the pandemic of 1918, in which an estimated 50 to 100 million people were killed (5). The most effective way to protect against influenza virus infection is through vaccination; however, current vaccination approaches rely on achieving a good match between circulating strains and the isolates included in the vaccine. Such a match is often difficult to attain due to a combination of Rabbit Polyclonal to NTR1 factors. First, Biricodar dicitrate (VX-710 dicitrate) influenza viruses are constantly undergoing change: every 3 to 5 5?years the predominant strains of influenza A viruses are replaced by variants that have undergone sufficient antigenic drift to evade existing antibody responses (6). Isolates to be included in vaccine preparations must therefore be selected each year based on the intensive surveillance efforts of the WHO collaborating centers. Second, to allow sufficient time for vaccine manufacture and distribution, strains must be selected approximately 9? months prior to the initiation of the influenza season. Unfortunately, the predictions of the vaccine strain selection committee can be inaccurate, resulting in a substantial drop in the efficacy of vaccination (7, 8). Herein, we describe a novel influenza vaccine construct which is based on a conserved region of the HA protein. The rationale for our approach follows (or builds on) from an earlier effort reported in 1983 (9), which in turn was prompted by our realization that the HA2 subunit of the influenza virus hemagglutinin is relatively well conserved (10). We reasoned that antisera elicited against the HA2 protein should be cross-reactive between strains and potentially cross-protective. However, during natural infection or vaccination with conventional influenza vaccines, HA2 is thought to be masked Biricodar dicitrate (VX-710 dicitrate) by the membrane-distal portion of HA, a bulky and highly immunogenic globular head domain. With the aim of producing a vaccine which would elicit cross-reactive anti-HA2 antibodies, we therefore derived a method of chemically treating purified influenza virions in order to remove the HA1 subunit. While immunization of rabbits or mice with subviral particles produced in this way yielded a strong humoral response against HA2, this response was?not found to be protective against influenza viral challenge (9). In the context of.