Intramuscular immunization of mice with live influenza virus is more immunogenic and offers greater protection than immunization with inactivated virus

Abstract

BackgroundInfluenza virus continues to cause significant hospitalization rates in infants and young children. A 2-dose regime of trivalent inactivated vaccine is required to generate protective levels of hemagglutination inhibiting (HAI) antibodies. A vaccine preparation with enhanced immunogenicity is therefore desirable.MethodsMice were inoculated intramuscularly (IM) with live and inactivated preparations of A/Wisconsin/67/2005 (H3N2). Serum cytokine levels, hemagglutinin (HA)-specific antibody responses and nucleoprotein (NP)-specific CD8+ T cell responses were compared between vaccinated groups, as well as to responses measured after intranasal infection. The protective efficacy of each vaccine type was compared by measuring virus titers in the lungs and weight loss of mice challenged intranasally with a heterosubtypic virus, A/PR/8/34 (H1N1).ResultsIntramuscular administration of live virus resulted in greater amounts of IFN-α, IL-12 and IFN-γ, HA-specific antibodies, and virus-specific CD8+ T cells, than IM immunization with inactivated virus. These increases corresponded with the live virus vaccinated group having significantly less weight loss and less virus in the lungs on day 7 following challenge with a sublethal dose of a heterosubtypic virus.ConclusionsInflammatory cytokines, antibody titers to HA and CD8+ T cell responses were greater to live than inactivated virus delivered IM. These increased responses correlated with greater protection against heterosubtypic virus challenge, suggesting that intramuscular immunization with live influenza virus may be a practical means to increase vaccine immunogenicity and to broaden protection in pediatric populations.

Qualitative Differences in T cell responses to Live, Attenuated and Inactivated Influenza Vaccines

“…The interactions and soluble factors elicited during initiation of the response are different for TIV and LAIV and would be expected to induce distinct CD4 + T cell types following immunization that may dictate the quality and quantity of the influenza-specific antibody response. This hypothesis is supported by findings of influenza studies in which distinct cytokines are elicited following different immunization regimes [13,14], with antibody responses that are in line with the paradigm that murine IgG1 responses are dependent on IL4-producing CD4 + T cells, and IFN-γ supports IgG2a responses [15]. A systems biology approach to compare human responses to LAIV and TIV showed increased amounts of mRNA for antiviral molecules in response to the infectious but not inactivated vaccine in circulating cells, and increased amounts of the chemokine IP-10 in plasma of individuals vaccinated with TIV but not LAIV recipients [16].…”

Sexual diergism in antibody response to whole virus trivalent inactivated influenza vaccine in outbred mice

“…Protection against disease is often not dependent on overall quantity of antibody response, but on the type of antibody response [14]. Thus, the titer of distinct subclasses of serum IgG was also examined.…”

Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization

“…However, due to the potential risk of attenuated vaccine strains to replicate in the lower respiratory tract, those in greatest need of vaccination, infants and the elderly, are excluded from using these vaccines. Harris et al [19] showed that live virus delivered by the non-productive IM route was much better at inducing virus-specific CD8 + T cell responses as well as protecting against heterologous challenge than inactivated virus given by the same route, suggesting that the use of live-virus immunisation may be a practical means of vaccinating paediatric populations to provide a breadth of protection.…”

“…Harris et al [19] showed that prevaccination of mice with live-virus via the IM route resulted in an increase in the CTL number after heterosubtypic challenge. The prevaccinated mice showed a 3-log reduction in lung viral load on day (d) 7 post-challenge compared to PBS pre-treated mice, indicating faster viral clearance.…”