Background: Influenza Virus, Immunity, and Vaccination

If an influenza pandemic began, emergency efforts to isolate the pandemic virus strain and prepare a vaccine from it would begin, while the pandemic spread. Should we pin our hopes on that race? On antiviral drugs? Or are there vaccines that could be made in advance and offer some degree of protection? Current vaccines focus on variable, strain-specific epitopes of circulating influenza virus strains and new viral strains require new vaccines. Here, a different approach will be considered, vaccination based on shared epitopes as an anti-infective measure that could provide broad protection against even new pandemic strains.

This review will draw together relevant observations from animal studies and from human epidemiology. In the venerable influenza field, some of the older literature is highly relevant to current questions in ways that were not considered at the time, so it must be revisited. After providing background on influenza infection and immunity, the review will focus on broad cross-protection against influenza A subtypes. It will explore the mechanisms of cross-protection in animals, the induction of cross-protection by vaccines of different types and their ability to protect against challenge with potential pandemic subtypes, such as H5N1. Finally, it will consider the possibility of broad immune cross-protection in humans and the public health implications for control of epidemics and pandemics.

Influenza remains a major public health problem. The World Health Organization (WHO) estimates that in a typical year, 10 to 20 percent of the world’s population is infected with influenza, resulting in 3,000,000 to 5,000,000 severe illnesses and 250,000 to 500,000 deaths (World Health Organization, 1999). In the United States, there are tens of thousands of deaths each year and the problem will increase due to the aging of the population and the susceptibility of the elderly.

During pandemics, the losses are even greater. The 1918 influenza pandemic was the most extreme, causing two billion cases, 20 to 40 million deaths worldwide and 500,000 in the United States, and killing with great speed. Young, healthy adults were not spared and approximately 80 percent of the U.S. Army’s World War I deaths were due to influenza (Wright and Webster, 2001). Pandemics in 1957 and 1968 also caused widespread disease and excess deaths. For further historical information, see Kilbourne (1975).

Vaccination is a highly successful strategy for controlling infectious diseases. It is cost-effective and population-wide campaigns are feasible. However, the pathogens against which vaccination has been most successful (e.g., smallpox and polio) have viral types that are few in number and genetically stable. With influenza virus, extensive genetic variation leads to the problem that different dominant viral strains circulate in the human population each year (Figure 5-1). The current vaccine system involves



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