Abstract
The use of vaccination against the influenza virus remains the most effective method of mitigating the significant morbidity and mortality caused by this virus. Antibodies elicited by currently licensed influenza vaccines are predominantly hemagglutination-inhibition (HI)-competent antibodies that target the globular head of hemagglutinin (HA) thus inhibiting influenza virus entry into target cells. These antibodies predominantly confer homosubtypic/strain specific protection and only rarely confer heterosubtypic protection. However, recent academia or pharma-led R&D toward the production of a “universal vaccine” has centered on the elicitation of antibodies directed against the stalk of the influenza HA that has been shown to confer broad protection across a range of different subtypes (H1–H16). The accurate and sensitive measurement of antibody responses elicited by these “next-generation” influenza vaccines is, however, hampered by the lack of sensitivity of the traditional influenza serological assays HI, single radial hemolysis, and microneutralization. Assays utilizing pseudotypes, chimeric viruses bearing influenza glycoproteins, have been shown to be highly efficient for the measurement of homosubtypic and heterosubtypic broadly neutralizing antibodies, making them ideal serological tools for the study of cross-protective responses against multiple influenza subtypes with pandemic potential. In this review, we will analyze and compare literature involving the production of influenza pseudotypes with particular emphasis on their use in serum antibody neutralization assays. This will enable us to establish the parameters required for optimization and propose a consensus protocol to be employed for the further deployment of these assays in influenza vaccine immunogenicity studies.
Highlights
INFLUENZA PSEUDOTYPES Influenza is a respiratory syndrome caused by three of six genera in the orthomyxoviridae family, influenza A, B, and C
The virion consists of a segmented negative sense genome encapsidated in ribonucleoprotein complexes, which are surrounded by a matrix shell and lipid envelope containing the two surface glycoproteins and the M2 ion channel
Influenza virus research is often hindered by the requirement for expensive biosafety precautions, especially in the case of the highly pathogenic avian influenza (HPAI, e.g. H5N1, H7N1) or pandemic strains
Summary
This review is a systematic analysis encompassing a wide range of peer-reviewed literature in English concerning the production and use of pseudotypes bearing influenza glycoproteins to date. This review will be useful to those interested in the production of pseudotypes for use in immunogenicity testing of preclinical influenza vaccines, whether in human or animal settings, and including “universal vaccine” candidates. Influenza serological studies such as the measurement of seroprevalence will benefit from this manuscript, which will help to inform the process of validation of pseudotype-based assays to clinical end-point. Studies utilizing chimeric HA proteins in order to differentiate between stalk and head directed antibodies will be discussed
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