We find that a single respiratory administration of replicationally inactivated influenza A viral particles most often elicits a waning serum antibody response, as the long-sustained bone marrow antiviral plasma cell populations characteristically induced by viral infection are lacking, though antiviral plasma cells at other sites may occasionally persist for a long time. To determine whether this alteration in the pattern of the B-cell response is a reflection of the nature of T-helper (Th) priming, we simultaneously primed B cells with inactivated influenza A/PR8(H1N1) and Th cells with infectious A/x31(H3N2). We show that Th cells cross-react extensively between these two viruses, although the antibody response to viral envelope glycoproteins is completely non-cross-reactive. Th cells primed by infectious A/x31 have little impact on the antibody response specifically elicted from naïve B cells by inactivated A/PR8 viruses, suggesting that the characteristic vigour of the antibody response to influenza viral infection depends on the direct interaction of antiviral B cells with virally infected dendritic cells. Memory B cells primed by inactivated influenza viral particles however, respond rapidly to secondary challenge with live or inactivated viruses, promptly populating bone marrow with antiviral plasma cells. Moreover, Th cells primed by previous live A/x31 viral challenge alter the pattern of the response of naïve B cells to live A/PR8 challenge by accelerating the appearance of anti-H1/N1 plasma cells in bone marrow, eliminating the early spike of anti-H1/N1 plasma cells in the mediastinal node, and generally diminishing the magnitude of the lymph node response. Inactivated A/PR8 and infectious A/x31 are both effective vaccines against A/PR8 infection, as mice preimmunized with either vaccine exhibit much more rapid viral clearance from the lung after infectious A/PR8 challenge. In fact, even when given during a course of anti-CD8 treatment to preempt cross-reactive cytotoxic T cells, live A/x31 is a more effective vaccine against A/PR8 infection than is inactivated A/PR8 itself.