Superior cross‐protective effect of nasal vaccination to subcutaneous inoculation with influenza hemagglutinin vaccine

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Abstract
Intranasal (i.n.) vs. subcutaneous (s.c.) administration of influenza hemagglutinin (HA) vaccine was systematically compared in BALB/c mice. Mice were immunized with different vaccines, together with cholera toxin B subunit as an adjuvant, and 4 weeks later were challenged with either a small (2 μl) or a large (20 μl) volume of mouse‐adapted A/Guizhou‐X (H3N2) virus, each of which gave virgin mice either a nasal or a lung predominant infection. Both i.n. and s.c. inoculations of A/Guizhou‐X vaccine conferred almost complete protection against both challenges. i.n. inoculation of A/Fukuoka (H3N2) or A/Sichuan (H3N2) vaccine conferred almost complete cross‐protection against 2‐μl challenge and a partial cross‐protection against 20‐μl challenge, whereas the s.c. inoculation conferred no cross‐protection against 2‐μl challenge with a partial cross‐protection against 20‐μl challenge. Moreover, i.n. immunization of PR8 (H1N1) vaccine gave a slight cross‐protection against 2‐μl challenge, while the s.c. inoculation did not. The degree of protection was easily improved by i.n. inoculation of higher doses of vaccine, but not by the s.c. inoculation. In parallel with the protection, the i.n. vaccination produced a high level of cross‐reacting IgA and IgG antibody to A/Guizhou‐X HA in nasal and broncho‐alveolar washes, while the s.c. vaccination produced the cross‐reacting IgG antibody alone. Thus, i.n. inoculation with inactivated vaccines, which induces crossreacting anti‐HA IgA antibody as well as IgG antibody, is more effective than s.c. vaccination for providing cross‐protection against drift viruses.