Subunit vaccines
Attempts to design and produce subunit vaccines have been prompted by a number of factors. Many viruses do not replicate easily or at all in cell culture, while others are considered to be too dangerous for use as live or killed vaccines, HIV being a prime example. There is also a risk that some vaccines may become latent in the body and subse- quently reactivate (e.g. HSV ) and of course some may simply be poorly effective or have unacceptable side effects (e.g. influenza virus vaccines).
The basis of the approach is to develop a vaccine product that represents an incomplete composite of viral antigens that, when injected into the host, will induce protective immu- nity against the virulent virus. The proteins of choice for such a vaccine are usually capsid or envelope proteins; often the protein that binds to the cell receptor such as gp120 of HIV or hemagglutinin (HA) of influenza. These proteins can be extracted from the virion by chemical treatment (influenza HA), concentrated from the plasma of infected patients and inactivated (hepatitis B surface antigen, HBsAg), engineered by recombinant DNA technology (HBsAg) or synthesized as a peptide such as the experimental peptide vaccine for foot and mouth disease virus, comprising part of the VP1 capsid protein of the virion.
These vaccines may suffer from some of the drawbacks of inactivated whole virus vaccines in that they do not replicate in the host. This limits their efficacy of immune stimulation and there is much research directed to the improved presentation and immunogenicity of virus subunit vaccines. Antigens may be injected with adjuvants, immune-stimulating agents such as aluminium oxide or the cholera toxin B subunit protein. Another approach is to conjugate the vaccine as a chimeric protein linked to host cytokines or even antibodies that enhance the immune response. Another approach under study at present is to introduce the selected viral gene into a virus vector such as the vaccinia virus. Immunization of the host with the replicating recombinant virus expresses a range of antigens including the protein encoded by the cloned gene. The goal is the stimulation of immunity to both the viral vector and the virus represented by the cloned gene. No such vaccine is licensed for human use, but a recombinant vaccinia virus expressing the rabies virus G protein is used for veterinary purposes.
Few subunit vaccines are in general use at present. The HBsAg induces strong protective immune responses and for many years was prepared by purifying the protein from the serum of infected individuals. The risk of infection with this preparation is now eliminated as the current vaccine involves purification of the protein from genetically engineered yeast cell cultures. The vaccine is used routinely to induce protection against HBV in members of the medical and scientific professions. A recently approved subunit vaccine (Gardasil, manufactured by Merck) is formed by the assembly of the two HPV structural proteins, L1 and L2, into capsid-like structures (known as virus-like particles, VLPs). The proteins are expressed in isolation, meaning that the VLPs contain no genome and hence are not infectious. Gardasil combines proteins from four strains of HPV, providing a broad protection vaccine that is aimed at young women to immunize against infection with high-risk HPV-6, -11, -16, and -18, which are strongly associated with cer- vical cancers.