Genetically Modified Viruses as Vaccines for SARS-CoV-2

One traditional vaccine strategy is to use weakened viruses to induce a protective immune response. A more recent approach is a viral vector platform whereby a separate virus is modified to contain a gene insertion encoding a viral protein from the pathogenic virus that the vaccine is designed to combat.

The viral vector has been modified to be low in pathogenicity and the vector has no relationship to gene it is designed to deliver. This engineered virus serves as a means to deliver the genetic code for an antigen, a protein that elicits a pathogen-specific immune response. The delivered genetic material is processed by cells to produce protein that triggers an immune memory. This intern protects the person upon exposure to the pathogen.

As of May 5, 2020, the World Health Organization listed eight vaccines currently being evaluated in humans for SARS-CoV-2, the virus that causes COVID-19; two of them use viral vector delivery platforms.[1]

Photo: Concept: A viral vector vaccine is a modified virus. It is constructed from a virus that is a modified, low pathogenic virus and a selected gene from a pathogen like SARS-CoV-2.

The viral vector vaccine approach has several merits. One key advantage is that because viral vector delivery mimics the process of viral infection, it prompts a potent immune response. This strategy can deliver the vaccine to both dividing and nondividing cells as well as selective cell types to elicit a robust and targeted immune response. The ability to target a wide range of cells during vaccination and ability to mimic actual viral infection boosts the immune response to the antigen produced from the vaccine viral vector. In contrast to protein-based vaccines that may use non-human cells during manufacturing, the viral vector vaccine platform uses human cells in the body to produce the antigens. Because the protein production, folding, and modification processes occurs in human cells, it closely mimics the antigen that would be produced by pathogenic infection. A more realistic antigen that induces pathogen-specific immune memory may confer superior protection.

Despite these merits, viral vector vaccines pose several challenges. One of the challenges is preexisting immunity to the virus being used as a viral vector due to prior exposure that yielded immune memory. Immune recognition and elimination of the viral vector will limit the delivery efficiency of the vaccine. This is an important consideration for repeated vaccine administration and dose determination in populations with prior exposure to the viral vector. Another challenge is the viral vector may elicit a robust inflammatory response, but this risk can be lessened by appropriate dosage. A final challenge with viral vector delivery is the strict regulations and high manufacturing costs that ensures products do not emerge with unintended viral properties.[2]

Adenovirus Vector Vaccine, Ad5-nCoV

CanSino Biologics Inc. and Institute of Biotechnology of the Academy of Military Medical Sciences partnered to make Ad5-nCoV, a viral vector called adenovirus type 5 (Ad5) vaccine for the novel coronavirus. CanSino applied the platform they used for an Ebola vaccine to deliver the spike protein of SARS-CoV-2.[3] Phase 1 results for the first 28 days after Ad5-nCoV vaccination show rapid induction of neutralizing antibodies and SARS-CoV-2 specific T cell responses.[4]

The results also tested trial participants prior to vaccination to look at existing immune response to Ad5. The study found reduced T cell responses, a portion of the immune response, among participants who had high antibody titers to Ad5. Boosting strategies for vaccination may be studied later to enhance the immune response in those that existing Ad5 immune responses.

The preliminary results of Phase 1 are promising. However, some participants experienced mild or moderate fever, fatigue, headache, and muscle pain, so Phase 2 will use the two lower doses that were tested in Phase 1. Phase 2 will assess the efficacy of the immune response elicited by the vaccine in a larger cohort.

Chimpanzee Adenovirus Oxford 1 Vector Vaccine, AZD1222

University of Oxford took their experience developing a vaccine for MERS-CoV and applied it to SARS-CoV-2.[5] Their approach utilizes a modified chimpanzee adenovirus Oxford 1 (ChAdOx1) vector to deliver the spike protein of SARS-CoV-2. ChAdOx1 is replication deficient virus that causes a common cold in chimps,[6] thus decreasing concern with preexisting human immunity to the viral vector. Astrazeneca partnered with University of Oxford on the project and renamed the vaccine AZD1222. The pharmaceutical company will help in making the vaccine widely available if it is safe and efficacious. Clinical trials have commenced, but data is not yet available.

The SARS-CoV-2 vaccine race has eight vaccines already in the clinic, including Ad5-nCoV and AZD1222 which use viral vector platforms to deliver a version of the spike protein. Despite potential challenges of preexisting immunity to the vector, induction of rampant inflammatory responses, and rigorous manufacturing processes, the protection include by this vaccine platform may be a game changer in fighting SARS-CoV-2.

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