Linda C. Lambert, Ph.D., and Anthony S. Fauci, M.D.
N Engl J Med 2010; 363:2036-2044
November 18, 2010
Each year, seasonal epidemics of influenza cause serious illness and death throughout the world. In the United States, the annual burden of disease is estimated to be 25 million to 50 million cases of influenza, resulting in an average of 225,000 hospitalizations. Over the past three decades, the estimated number of influenza-associated deaths per year in the United States has ranged from 3349 to 48,614. The majority of deaths (>90%) occur among elderly persons, usually those with chronic underlying health conditions.1-3 The World Health Organization uses these estimates to extrapolate a likely global disease burden from influenza of up to 1 billion infections, 3 million to 5 million cases of severe disease, and between 300,000 and 500,000 deaths annually.1 Pandemics of influenza with varying rates of illness and death have occurred throughout history; the most notable was the 1918–1919 pandemic, which claimed an estimated 50 million to 100 million lives worldwide.4
First isolated from humans in 1933,5 influenza viruses contain 8 single-stranded RNA segments encoding 11 proteins (Figure 1Figure 1Structure and Replication Cycle of Influenza A Virus and Well-Characterized Adaptive Immune Responses.). There are three types of influenza viruses: A, B, and C, with types A and B causing annual human epidemics. A key feature of the influenza virus is its error-prone polymerase, which results in an accumulation of genetic mutations that are selected for in hemagglutinin (HA) and to a lesser extent neuraminidase (NA) — the major surface glycoproteins of the virus. This antigenic drift of the HA protein renews our susceptibility to influenza viruses and is the basis for frequent updating of the composition of seasonal influenza vaccines. Protection after natural infection is primarily mediated by HA-specific antibodies in serum and mucosa, with the presence of antibodies against NA, conserved influenza proteins, and T-cell responses correlating with reduced disease severity.