Why is timing crucial for smallpox post-exposure vaccination?

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Timing matters because the vaccine must trigger the immune response before the variola virus has progressed too far. The smallpox vaccine is a live vaccine that starts an immune reaction that takes several days to develop. If vaccination is given soon after exposure, this immune response can be ready to confront the virus as it begins to replicate, which can prevent illness or lessen its severity. Delaying vaccination allows the virus to replicate unchecked longer, making it much less likely that the vaccine can alter the course of disease. That’s why a short post-exposure window is most effective—the sooner after exposure, the greater the chance to prevent disease or reduce severity.