Vectorized vaccine

Vector vaccines are vaccines based on viral vectors. They represent a promising and innovative alternative to the "classical" vaccines. They are mainly needed for "novel" pathogens against which no effective therapeutics are yet available. The repeated successful testing of the VSV-ZEBOV vaccine vector in eastern Congo shows that vector-based vaccines are already capable of making an important contribution to the containment of dangerous epidemics.

A distinction is made:

• Replicating vector vaccines also produce new virus particles in the cells they infect. These then infect new cells, which also produce the vaccine antigen.
• Non-replicating vector vacc ines cannot produce new virus particles. They only produce the vaccine antigen.

In vector virus vaccines, the viral genetic material of a pathogenic virus is incorporated into proven harmless carrier virus es and injected as a vaccine. The harmless vector virus multiplies in the vaccinated organism, but without "pathogenic" consequences. In the process, it forms exactly those proteins that are important for the antigenicity of the pathogenic virus (or of a tumour parenchyma). The immune system of the organism then produces the desired protective antibody. Due to the diverse biological properties of the different vector systems, it is in principle possible to deliberately direct the type of vaccine antigen-specific immune response in a specific direction. This opens up different design possibilities for the encoded immunogens. These can be expressed intracellularly, membrane-bound or as secreted molecular molecules. For example, the recombinant replication-competent Ebola vaccine VSV-ZEBOV uses the "vesicular stomatitis virus" VSV as a vector. In VSV, the glycoprotein G of VSV was exchanged for the Ebola glycoprotein.

Viral vectors: Viral vaccine vectors can be either replication-competent (e.g. the VSV-ZEBOV vector) or replication-incompetent (e.g. adenoviral vectors). Suitable vectors include RNA viruses (e.g., VSV or measles viruses) or DNA-based viruses (e.g., poxviruses or adenoviruses). Vector viruses can be enveloped (e.g. VSV or poxviruses) or non-enveloped (e.g. adenoviruses). An important requirement of viral vectors is their ability to express the target proteins correctly folded and glycosylated. Only in this way can an efficient antiviral antibody response be expected. Various enveloped viruses are also capable of incorporating the foreign glycoprotein into their envelope (Bresk CA et al.2019). A variety of different viruses have now been developed to produce viral vaccine vectors (Afrough B et al. 2019).

Examples of diseases for which vector virus vaccines (V) are available have been developed against HIV, against further filo viruses (Marburg virus), against corona viruses (SARS/MERS) and against flaviviruses (e.g. Zika virus). Since 2015, a polyvalent dengue virus vaccine (Denvaxia®) based on a genetically modified, attenuated Gelbfieber virus has been used. In addition to Ebola, it is primarily other viruses against which vector-based vaccines are being developed. These include HIV, other Filo viruses (Marburg), Corona viruses (SARS/MERS) and Flavi viruses (e.g. Zika virus). Since 2015, the polyvalent dengue virus vaccine, which is based on a genetically modified, attenuated Gelbfieber virus, has also been used in endemic areas. In the case of Zika virus, experimental approaches to a vectorized vaccine demonstrate that it is capable of generating appropriate antibody production (López-Camacho C et al. 2019). In the oncological field, the oncofetal antigen 5T4 is an interesting antigenic target surface glycoprotein expressed on a variety of human adenocarcinomas but rarely on normal tissues. Vaccinia virusAnkara (MVA) was chosen as the viral vector and modified to encode human 5T4, making the vectorized vaccine 5T4 antigenically active (Kim DW et al. 2010).

The choice of vaccine vector, combination partners and antigens may also determine the nature of the immune response. For example, early HIV vaccine studies used recombinant envelope proteins with the goal of inducing broadly neutralizing antibodies (Vax003 and Vax004 studies). Later, HIV genes containing low variable immunodominant T cell epitopes (gag, pol, nef) but not the highly variable HIV envelope protein Env were selected. This T cell-based vaccination strategy was unfortunately not successful (Gray G et al. 2010).

The problem with vector-specific immune responses: An important factor that may limit the efficiency of many viral vaccine vectors is vector-specific immunity mediated by antibodies and/or T cells. This would possibly also affect their safety profile. In general, however, little research has been done in humans on how long and how strongly vector-specific immunity affects subsequent vaccinations (Joachim A et al 2017).

Viral vaccine vectors are usually constructed in such a way that they do not integrate into the genome of the target cell. This minimizes the risk of insertional mutagenesis. Furthermore, most viral vaccine vectors express the vaccine antigens in the patient only transiently. However, this time span is usually sufficient to induce efficient immune responses.

1. Agnandji S T et al. (2016) Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe. The New England journal of medicine 374: 1647-1660.
2. Afrough B et al. (2019) Emerging viruses and current strategies for vaccine intervention. Clin Exp Immunol 196: 157-166.
3. Barouch DH et al. Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 392: 232-243.
4. Bresk CA et al.(2019) Induction of Tier 1 HIV Neutralizing Antibodies by Envelope Trimers Incorporated into a Replication Competent Vesicular Stomatitis Virus Vector. Viruses 11: 2
5. Gränicher G et al. (2020) Production of Modified Vaccinia Ankara Virus by Intensified Cell Cultures: A Comparison of Platform Technologies for Viral Vector Production. Biotechnol J 6:e2000024.
6. Gray G et al. (2010) Overview of STEP and Phambili trial results: two phase IIb test-of-concept studies investigating the efficacy of MRK adenovirus type 5 gag/pol/nef subtype B HIV vaccine. Current opinion in HIV and AIDS 5: 357-361.
7. Henao-Restrepo AM et al.(2017) Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ca Suffit!). Lancet 389: 505-518.
8. Joachim A et al (2017) Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers. AIDS research and human retroviruses 33: 880-888.
9. Kim DW et al. (2010) TroVax, a recombinant modified vaccinia Ankara virus encoding 5T4: lessons learned and future development. Hum Vaccin 6:784-791.
10. López-Camacho C et al. (2019) Assessment of Immunogenicity and Efficacy of a Zika Vaccine Using Modified Vaccinia Ankara Virus as Carriers. Pathogens 8: 216.
11. Ondondo B et al.( 2016) Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection. Mol Ther 24: 832-842.