Viral vector vaccines - why doesn't the viral vector get attacked by the innate immune system?

Question

I've been looking at how the Astrazeneca Covid-19 vaccine works:

A chimpanzee adenovirus (the viral vector) is injected into the patient. After entering a cell, the viral DNA is deposited in the host cell nucleus.

• The viral DNA only contains information about the SARS-CoV-2 spike protein.
• The viral DNA does not integrate with the host cell DNA.

mRNA is transcribed from the viral DNA, and this mRNA is translated into the SARS-CoV-2 spike protein. This is displayed on the surface of the cell where it is recognised as an intruder by the immune system which then begins producing antibodies.

Pre-existing immunity is recognised as a potential problem. From Medical News Today - COVID-19: How do viral vector vaccines work?:

With all viral vectors, one issue to consider is pre-existing immunity. If a person encountered the virus that serves as the vector in the past, they may have antibodies to the virus. This means that their body will try to fight and destroy the viral vector, potentially making a vaccine less effective.

But where is the innate immune system in all this? My (layman's) understanding is that the very fact that the virus particle was novel would result in an immediate response from the innate immune system. How does the viral vector get past it?

Answer 1

These Chimpanzee adenoviral vectors do not bypass the innate immune system at all. In fact they are used precisely because of their activation of the innate immune system, which then results in greater immunity because activation of the innate immune system results in antigen presentation and then activation of the adaptive immune system.

The reason they activate the innate immune system is because these viruses do not have a seroprevalence, so they can only activate the innate immune response with an end result of antigen presentation. In contrast, human adenovirus vectors generally have a high seroprevalence (because we've all had colds caused by adenoviruses), so they activate the adaptive immune response against the viral particle (vector), clearing it before presentation of the novel antigen (in this case the CoV spike protein) can occur.

There's a nice commentary on the different mechanisms by which the ChAdOx1 (Astrazenica/Oxford) and the mRNA (Moderna/Pfizer) vaccines work at Nature Reviews Immunology. To quote the relevant paragraph (emphasis mine):

The AdV vaccines also contain inherent adjuvant properties, although these reside with the virus particle that encases the DNA encoding the immunogen. Following injection, AdV particles target innate immune cells like DCs and macrophages and stimulate innate immune responses by engaging multiple pattern-recognition receptors including those that bind dsDNA — in particular TLR9 — to induce type I interferon secretion8. Unlike AdV vectors, mRNA vaccines do not engage TLR9, but both vaccine formulations converge on the production of type I interferon (Fig. 1). Type I interferon-producing DCs and other cells that have taken up the vaccine-derived nucleic acids encoding the S protein can deliver both an antigenic and inflammatory signal to T cells in LNs draining the injection site. This activates S protein-specific T cells and mobilizes adaptive immunity against SARS-CoV-2

One of the problems with using a simian adenovirus vector like the ChAdOx1 vector is that now a large portion of the population will have some antibody response to the vector (as well as the introduced spike), so future uses of this same vector might not result in as high an immune response as we have seen this time around, when the population is almost entirely naive.

Answer 2

The innate immune system has many different components to it. If we consider a natural virus, like the base adenovirus used as a vector used in the Oxford/AstraZeneca vaccine, then we can assume that the virus already has sufficiently effective strategies in place to deal with them.

In particular:

• Physical and chemical barriers are irrelevant, given an injected vaccine.
• Interferon and MHC pathways must already be either ineffective or slow enough to be secondary in the response against the adenovirus's foreign proteins, such that NK cells shouldn't be expected to change their efficacy.
• The vaccine protein isn't expected to damage the cell membrane, so that pathway won't change either.
• Inflammation and antibacterial pathways aren't triggered by presentation of an extra protein either.
• Activation of the adaptive immune system through antigen presentation is exactly the sort of response that is desired.