Recombinant vector vaccines retain many advantages of live attenuated vaccines

In this article, I briefly describe the recombinant vector vaccines and their advantages over live attenuated vaccines.

Table of Contents

Live attenuated vaccines

Attenuation is a process, where microorganisms lose their ability to cause a significant disease. In other words, attenuation takes away the pathogenicity of microorganisms. Attenuation can be achieved when a pathogenic virus or bacterium is grown under abnormal culture conditions for a prolonged period. These attenuated microorganisms have developed a habit of growing in abnormal culture conditions, and therefore have less possibility of growth in the natural host. Killed or inactivated vaccines often require repeated boosters to get a protective immunity. As inactivated vaccines do not replicate in the host, they induce a humoral response rather than a cell-mediated one. However, live attenuated vaccines require a single dose to induce long-lasting immunity. Attenuated vaccines can replicate within host cells. Thus, they are suitable for eliciting a cell-mediated response.

A major disadvantage of attenuated vaccines is that they can revert to a virulent form. In rare cases, when there is inadequate vaccination of the population, natural mutations during viral replication, or interference by related viruses, can cause an attenuated virus to revert to its wild-type form or mutate to a new strain, potentially resulting in the new virus being infectious or pathogenic.

Recombinant vector vaccines

Live vaccines replicate within the host and can be broadly categorized into two main types: attenuated and recombinant-vectored vaccines. Most live viral vaccines in use today are attenuated vaccines. Their reduced virulence is usually achieved by adapting the wild-type virus to a different environment, such as growing it in a novel cell line or under low-temperature conditions. This adaptation leads to a decreased replication rate in humans.

Using attenuated vaccines for pathogens like HIV is considered too risky. A safer approach involves developing live recombinant vector vaccines. These vaccines are live, replicating viruses that are genetically engineered to include one or more genes from the pathogen. These added genes encode proteins with immunogenic properties, which help stimulate protective immunity. Genes that encode major antigens of virulent pathogens can be introduced into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen. Since the pathogen is devoid of most of its genome, it can’t revert to its pathogenic form.

Recombinant virus vector vaccines represent a key emerging technology in vaccine development. These vaccines are capable of producing antigens in vivo for an extended duration. The antibodies generated can either be secreted from the host cell to trigger humoral immunity or presented via MHC-I molecules to activate a cellular immune response. The expressed antigens can take various forms. The process closely mimics the natural infection cycle of pathogens, resulting in enhanced and robust immunogenicity. Several organisms have been utilized as vectors for these vaccines, including vaccinia virus, canarypox virus, attenuated poliovirus, adenoviruses, attenuated salmonella strains, the BCG strain of Mycobacterium bovis, and specific strains of Streptococcus naturally found in the oral cavity.

Vaccine production using a recombinant vaccinia vector

Vaccinia virus, a large complex virus, with a genome of about 200 genes, has been widely employed as a vector for the design of new vaccines to eradicate smallpox. It can be engineered to carry several dozen foreign genes without impairing its capacity to infect host cells and replicate. A vaccinia vector is genetically engineered that carry a foreign gene from another pathogen. It expresses elevated levels of the inserted gene product, which can then serve as a potent immunogen in an inoculated host.

In the production of the vaccinia vector vaccine (figure-1), the gene encoding the desired antigen is inserted into a plasmid vector adjacent to a vaccinia promoter. It is flanked on either side by the vaccinia thymidine kinase (TK) gene. When the vaccinia virus and the recombinant plasmid are incubated simultaneously with tissue culture cells, the antigen gene and promoter are inserted into the vaccinia virus genome by homologous recombination at the site of the nonessential TK gene, resulting in a TK- recombinant virus. Cells with the recombinant vaccinia virus are selected by the addition of bromodeoxyuridine (Budr), which kills TK⁺ cells.

**Figure 1: Vaccine production by a recombinant vaccinia vector**

Vaccinia vector vaccines, created through genetic engineering, can be easily delivered by scratching the skin. It leads to a localized infection in host cells. When the foreign gene encoded by the vaccinia vector produces a viral envelope protein, it becomes embedded in the membrane of the infected host cells. This triggers the activation of both cell-mediated and antibody-mediated immune responses.

Other viruses and bacteria in the production of vaccine

The canarypox virus, a relative of vaccinia is large and easily engineered to carry multiple genes. It is not virulent like vaccinia even in individuals with severe immune suppression. An attenuated strain of the bacterium Salmonella typhimurium has been engineered with genes from the bacterium that causes cholera. Salmonella infects cells of the mucosal lining of the gut and thus induces the production of secretory IgA. When immunity is elicited at the mucosal surface, it could provide excellent protection at the portal entry for many common infectious agents, like gonorrhea and cholera.

Conclusion

Genes that encode major antigens of virulent pathogens can be introduced into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen. Since the pathogen is devoid of most of its genome, it can’t revert to its pathogenic form.

Vaccinia virus, a large complex virus, with a genome of about 200 genes, has been widely employed as a vector for the design of new vaccines to eradicate smallpox. A vaccinia vector is genetically engineered that carry a foreign gene from another pathogen. It expresses elevated levels of the inserted gene product, which can then serve as a potent immunogen in an inoculated host.