Jpn. J. Infect. Dis., 58 (4), 195-207, 2005

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Review

Mechanisms of Broad Cross-Protection Provided by Influenza Virus Infection and Their Application to Vaccines

Shin-ichi Tamura*, Takeshi Tanimoto and Takeshi Kurata1

Laboratory of Prevention of Viral Diseases (Research Foundation for Microbial Diseases of Osaka University), Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871 and 1Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

(Received February 10, 2005. Accepted June 6, 2005)


*Corresponding author: Present address: Department of Pathology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. Tel: +81-3-5285-1111, Fax: +81-3-5285-1189, E-mail: stamura@nih.go.jp


CONTENTS:
1. Introduction
1-1. Characteristics of influenza
1-2. Viral antigens involved in immunity
1-3. Defense Mechanisms against Influenza
1-4. Purpose of this review
2. Mechanisms inducing subtype-specific or heterosubtypic immunity
2-1. Mechanism of subtype-specific protection
2-2. Mechanism of heterosubtypic protection
2-3. Kinetics of subtype-specific or heterosubtypic protection
2-4. Cross-protection against re-infection in humans infected previously with variant viruses
3. Cross-protection provided by current vaccines
3-1. Parenteral inactivated vaccine
3-2. Live attenuated virus vaccine
4. Cross-protection provided by new vaccines
4-1. Inactivated vaccine
4-1-1. Parenteral adjuvant-combined vaccine
4-1-2. Non-parenteral vaccine
4-1-2-1. Nasal split-product or whole-virion vaccine
4-1-2-2. Adjuvant-combined nasal inactivated vaccine
4-1-2-3. Epidermal immunization vaccine
4-1-3. Improved vaccine constituents
4-1-3-1. Neuraminidase
4-1-3-2. Conserved HA epitope
4-1-3-3. M2 protein
4-1-4. DNA vaccine
4-2. Live virus vaccine
4-2-1. Recombinant live virus vaccine
4-2-2. Virus-vectored vaccine
5. Perspectives for the development of new influenza vaccines using mice

SUMMARY: Mice recovered from influenza A virus infection have been shown to be cross-protected against challenge infection with either drift viruses within a subtype (subtype-specific immunity) or different subtype viruses (heterosubtypic immunity). The mechanisms of broad-spectrum of cross-protection could be explained as follows. (i) Pre-existing S-IgA and IgG antibodies (Abs) induced by infection are involved in the elimination of challenge viruses by forming virus-Ig complexes shortly after re-infection. Due to their polymeric nature, the S-IgA Abs, existing more abundant on the mucosa than are IgG Abs, are strongly cross-reactive with challenge viruses, whereas the IgG Abs are weakly cross-reactive with challenge viruses, due to their monomeric nature. The specificity of Abs is directed mainly at hemagglutinin and neuraminidase. (ii) CD8+ memory T cells induced by infection are involved in the elimination of challenge viruses by the accelerated killing of host cells infected with different subtype viruses from day 3 onwards after re-infection. The specificity of memory T cells is directed against viral internal proteins. (iii) The accelerated IgA and IgG Ab responses, produced by B memory cells after a challenge, are also involved in cross-protection from day 4 onwards after re-infection. (iv) In the epithelial cells of infected mice, dimeric IgA that is trafficked through the epithelial cells can contribute to the prevention of viral assembly by binding to newly synthesized viral proteins. Natural infection is well known to be superior to parenteral inactivated vaccines in inducing the broad-spectrum cross-protection. To improve the efficacy of current inactivated vaccines, many trials have been conducted to mimic natural infection, including intranasal or epidermal administration of inactivated vaccine with or without an adjuvant; such studies are still ongoing. In the near future, some of these trials may provide new, safer and more effective broad-spectrum vaccines than those currently available.


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