Priming for pandemic influenza: thanks for the memories.

Pandemic influenza remains a continuing global threat, and in the past 10 years we have seen 2 avian influenza viruses spread into the human population and a pandemic of a novel triple-reassortment influenza A(H1N1). Since reemerging in 2003, avian influenza A(H5N1) is now widely dispersed among birds, and >600 human cases of infection with high case-fatality rates have been reported worldwide [1]. The most recent threat, and perhaps the most concerning to date, is an avian influenza A(H7N9) strain first reported from China in March 2013 [2]. Cases continue to accumulate in China, and most illnesses are severe, with a death rate of approximately 33%. Infection is believed to be due to contact with infected poultry, and at the present time there is no evidence of sustained human-to-human transmission, although limited person-to-person spread has been noted. Vaccination remains the cornerstone of any pandemic preparedness plan. The speed at which the pandemic influenza A (H1N1) strain spread across our interconnected world in 2009 clearly illustrates the need for rapidly deployable, effective vaccines. There are now global networks in place to identify new threats as early as possible, and methods to hasten and improve the efficiency of vaccine production have been developed. However, the time it takes to develop a protective immune response remains a key issue. Mathematical modeling indicates that the maximum reduction in viral transmission would be achieved by a vaccine capable of inducing a protective immune response within 2 weeks after the outbreak of the pandemic [3]. Unfortunately, the primary immune responses to novel antigens in the form of inactivated subvirion influenza vaccines (ISIVs) have been poor, requiring high doses of antigen and repeated immunizations [4]. The use of adjuvants can improve the primary immune response in virus-naive persons; however, multiple doses and time to develop protective immunity are still usually required [5, 6]. Of note, the immune response to primary immunization with 2009 influenza A(H1N1) was substantially better than what had been previously observed in influenza A(H5) vaccination trials. During the initial influenza A(H5) vaccine trials, two 90-μg doses of influenza A(H5N1) ISIV were found to be only modestly immunogenic in virus-naive subjects, whereas, a single 15-μg dose of 2009 influenza A(H1N1) ISIV induced protective titers of >1:40 in 95% of subjects [4, 7]. In addition, individuals born prior to 1957 were relatively protected from the 2009 pandemic influenza A (H1N1) strain [8]. Although the 2009 influenza A(H1N1) strain was very antigenically distinct from the previously circulating seasonal influenza A(H1N1) strain, these observations suggest that the population possessed some degree of immunologic memory to this new strain of influenza from prior influenza A (H1N1) infections or vaccinations. It is well known that memory responses to previously encountered pathogens are quantitatively and qualitatively different than primary antibody responses. Switching to mature isotypes with higher affinity occurs, and a greater diversity of antibody is typically produced. Increased affinity for antigen and increased expression of major histocompatibility class II and costimulatory molecules facilitate antigen uptake, allowing memory B cells to initiate critical interactions with helper T cells at lower doses of antigen. However, the precise mechanisms involved and the specific cell types that are important for the successful development of memory are not well defined. Since memory immune responses are clearly superior to primary responses, an understanding of Received 23 February 2014; accepted 25 February 2014; electronically published 5 March 2014. Correspondence: Ann R. Falsey, MD, Infectious Disease Unit, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621 ([email protected]). The Journal of Infectious Diseases 2014;209:1857–9 © 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: journals. [email protected]. DOI: 10.1093/infdis/jiu124