Elsevier

Vaccine

Volume 23, Supplement 1, 8 July 2005, Pages S26-S38
Vaccine

Review
The virosome concept for influenza vaccines

https://doi.org/10.1016/j.vaccine.2005.04.026Get rights and content

Abstract

There is a need for more efficacious inactivated influenza vaccines, since current formulations show suboptimal immunogenicity in at-risk populations, like the elderly. More effective vaccines are also urgently needed for an improved influenza pandemic preparedness. In this context, there is considerable interest in virosomes. Virosomes are virus-like particles, consisting of reconstituted influenza virus envelopes, lacking the genetic material of the native virus. Virosomes are produced from influenza virus through a detergent solubilization and removal procedure. Properly reconstituted virosomes retain the cell binding and membrane fusion properties of the native virus, mediated by the viral envelope glycoprotein haemagglutinin. These functional characteristics of virosomes form the basis for their enhanced immunogenicity. First, the repetitive arrangement of haemagglutinin molecules on the virosomal surface mediates a cooperative interaction of the antigen with Ig receptors on B lymphocytes, stimulating strong antibody responses. In addition, virosomes interact efficiently with antigen-presenting cells, such as dendritic cells, resulting in activation of T lymphocytes. In a murine model system, virosomes, as compared to conventional subunit vaccine, which consists of isolated influenza envelope glycoproteins, induce a more balanced T helper 1 versus T helper 2 response, virosomes in particular eliciting stronger T helper 1 responses than subunit vaccine. Also, as a result of fusion of the virosomes with the endosomal membrane, part of the virosomal antigen gains access to the major histocompatibility class I presentation pathway, thus priming cytotoxic T lymphocyte activity. Finally, virosomes represent an excellent platform for inclusion of lipophilic adjuvants for further stimulation of vaccine immunogenicity. By virtue of these characteristics, virosomes represent a promising novel class of inactivated influenza vaccines, which not only induce high virus-neutralizing antibody titres, but also prime the cellular arm of the immune system.

Section snippets

Key messages

  • Despite the established efficacy of current inactivated influenza vaccines, there is an urgent need for improved flu vaccine formulations.

  • In the face of pandemic threat, new influenza vaccines need to induce robust virus-neutralizing antibody responses in immunologically naïve individuals.

  • Declining T cell functions with age require that new vaccines for the elderly not only induce solid antibody responses but also stimulate cell-mediated immunity.

  • Virosomes are reconstituted influenza virus

Background

Influenza continues to affect thousands of people each year causing epidemics with severe morbidity and considerable excess mortality, the latter particularly among the elderly [1], [2], [3]. Outbreaks are also associated with high economic costs to society [4], [5]. Furthermore, there is increasing concern about a potential new influenza pandemic, since highly pathogenic avian influenza viruses, such as the H5N1 virus currently circulating in South-East Asia, have the ability to cross the

Background

Virosomes represent a novel vaccine presentation form that closely mimics the native virus. Virosomes are virus-like particles, consisting of reconstituted viral envelopes, lacking the viral genetic material. They are generated from virus by a detergent solubilization and reconstitution procedure [40], [41], as discussed in more detail below. Virosomes may be produced from a variety of enveloped viruses, including influenza virus, the resulting particles being similar to the original virus in

Interaction of virosomes with B lymphocytes and antigen-presenting cells

Fig. 5 depicts schematically how virosomes probably interact with cells of the immune system, in particular B lymphocytes and dendritic cells. Haemagglutinin and neuraminidase spikes protruding from the virosomal membrane, as well as foreign antigens that may be coupled to the surface of the virosomes (see below), can be recognized by membrane-associated immunoglobulin receptor molecules on B lymphocytes [56]. The repetitive arrangement of the antigens on the virosomal surface presumably

Antibody responses to influenza

Virosomal influenza vaccines have been extensively investigated in humans. In fact, a virosomal influenza vaccine has been commercially available for a number of years (Inflexal V®, Berna Biotech, Berne, Switzerland). Clinical studies have demonstrated that intramuscular administration of this virosomal influenza vaccine to humans induces haemagglutination-inhibition (HI) titres at least similar to those induced by conventional whole virus or subunit vaccines [64], [65]. Another virosomal

Background

As indicated above, CTLs are responsible for the destruction of virus-infected cells and thus for the clearance of virus infections [58]. In humans, influenza-specific CTLs are mainly directed against epitopes derived from internal proteins of the virus, such as the matrix protein and the nucleoprotein, while in mice immunodominant epitopes are found predominantly on the nucleoprotein [76]. However, other viral antigens including haemagglutinin may also induce biologically relevant CTL

Background

Adjuvants are substances that enhance the immune response. Some adjuvants, like the commonly used aluminium salts or mineral oil serve to form a physical depot retaining the antigen for presentation to cells of the immune system. While stimulating antibody responses, aluminium adjuvants do not effectively augment CTL responses. More sophisticated adjuvants are recognized by receptors on antigen-presenting cells. Engaging of these receptors results in intracellular signalling and in the

Concluding remarks

The suboptimal efficacy of current inactivated influenza vaccines in elderly people as well as the threat of a new influenza pandemic underline the urgent need for more efficacious inactivated flu vaccine formulations. The requirements for such novel vaccines are, however, somewhat divergent. While improvements of vaccines for the elderly are sought primarily at the level of cell-mediated immunity, the most important requirement for pandemic vaccines involves the ability to induce a robust

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