This year marks a somber anniversary: the centennial of the 1918 Spanish influenza pandemic, which claimed nearly 100 million lives worldwide in one of the deadliest disease outbreaks in recorded history. This pandemic was so severe that it caused life expectancy in the United States to fall by ∼12 y. The death rate in those between the ages of 20 and 40 y old was unusually high; this change in the demographics would leave a lasting impact on the world for years to come (1).

The centennial commemoration of this epidemic comes at a time when the shortcomings of our seasonal approach to influenza (flu) vaccination are on center stage. This moving target of a pathogen may affect us all in several ways. We may become ill ourselves, we may experience the illness of those around us, or we may even suffer the tragic loss of a loved one.

To acknowledge this significant anniversary, I am proud to introduce “Immunity to Influenza: Closing in on a Moving Target,” the third annual topical issue of Brief Reviews published in The Journal of Immunology. The issue includes nine Brief Reviews that highlight some of the most important aspects of our quest to conquer this elusive virus. It is my hope that, through this panoramic perspective, readers will gain a deeper appreciation for how studies of flu infection and viral escape mechanisms can lead to strategies for inducing lifelong immunity.

This special issue begins with an overview by Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases. Together with Paules and McDermott (2), Fauci describes the successes and challenges of our current seasonal vaccine approach in combatting the flu virus. The authors briefly review how an individual’s initial exposure to the flu virus might have a lifelong impact on immune responses to vaccines or related strains (original antigenic sin). They go on to discuss immunity to specific flu Ags and how this immunity could potentially drive efforts toward a universal vaccine.

Miller and colleagues (3) explore the evidence for original antigenic sin. The authors discuss how certain Ag-specific Abs may contribute to this protective mechanism through cross-reactivity to drifted strains of the virus. In addition, they pose several vexing questions for understanding the lasting impact of original antigenic sin, including how routes of antigenic exposure or specific B and T cell epitopes affect infection and vaccination outcomes.

Scientists have long appreciated that viral factors are important determinants of immune evasion and illness severity. Gounder and Boon (4) review how factors intrinsic to the host, such as sex, age, pregnancy, genetics, obesity, and commensal microbes, might influence protection or disease severity.

Next, three reviews explore how different cell subsets and their products control flu infection and contribute to long-lasting immunity. It is clear that B cells and Abs are central to flu control and memory. Lam and Baumgarth (5) review production of protective, neutralizing Abs, but also discuss the ever-expanding roles B cell subsets play in flu protection and pathogenesis. These roles include responses to and expression of cytokines, the functions of innate-like B cell subsets, and the relative importance of germinal center reactions and extrafollicular plasmablasts in generating robust and durable immunity.

Crowe (6) delves deeper into the conventional role of B cells by covering our current understanding of Ab repertoires that develop in response to flu infections or vaccinations. He discusses how classical methods and, more recently, next-generation sequencing, have been applied to significantly extend our knowledge of repertoire diversity, as well as flu Abs shared by many individuals (public clonotypes). Such information should be critical in our quest to decipher which Ab responses are most effective at pathogen neutralization, clearance, and the provision of lasting immunity in a diverse human population.

A key cell type for promoting B lymphocyte responses is the T follicular helper (TFH) cell subset. Koutsakos, Nguyen, and Kedzierska (7) review the role of TFH cells in coordinating germinal center responses to flu vaccines. These responses ultimately determine the effectiveness of Abs and the generation of memory B cells and long-lived plasma cells. The authors also discuss the recent discovery that human TFH cells are found in circulation. This finding enables exciting paths to understanding aspects of TFH–B cell cross-talk that produce optimal responses to the virus, especially with regard to individuals at high risk of adverse outcomes.

Pizzolla and Wakim (8) focus on how memory T cells residing in airway tissues contribute to acute and long-term flu protection. Importantly, because many of the respiratory T resident memory cells appear to recognize Ags that are conserved across viral strains, they may be essential to designing vaccines with broad immunity by acting at the point of viral entry.

Our approaches to understanding flu pathogenesis in humans also will benefit from studies of other closely related viruses. Koutsakos, Kedzierska, and Subbarao (9) review our current knowledge of one such pathogen, the avian flu virus, which only sporadically infects humans but has pandemic potential if emergent mutants spread more efficiently in people. The authors also describe ongoing efforts to design an avian flu vaccine.

The discussion of a universal flu vaccine by Fauci and colleagues comes full circle with the final review in our series. Estrada and Schultz-Cherry (10) discuss the relative merits of various vaccine platforms, including antigenic targets, production methods, adjuvants, and delivery modes. The authors then describe how optimization of these factors might drive the development of a universal vaccine.

Collectively, the perspectives and information in these Brief Reviews highlight a foundation for future collaborations between immunologists and virologists that will move us closer to a universal, durable flu vaccine. Our continuously expanding knowledge also provides an opportunity to advance public awareness about the benefits of vaccines to many human pathogens, while dispelling misconceptions about possible side effects. We have come a long way in the 100 y since the tragic 1918 flu epidemic. The tremendous advances made by scientists give us hope that we will soon celebrate the development of a universal vaccine to rid our lives of this persistent and elusive pathogen.

St. Louis Red Cross Motor Corps on duty during October 1918 flu epidemic. St. Louis, MO. Photograph retrieved from the Library of Congress (https:www.loc.gov/item/2011661525/).

St. Louis Red Cross Motor Corps on duty during October 1918 flu epidemic. St. Louis, MO. Photograph retrieved from the Library of Congress (https:www.loc.gov/item/2011661525/).

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1
Centers for Disease Control and Prevention. Remembering the
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