Antibody detection - infection-induced vs vaccine-induced - is it common (or not) for a test to be positive for both?

Question

Given a pathogen and a corresponding vaccine, and given an immune response to either one that results in antibody creation, would it be expected that a clinical test or assay for said antibodies would find it difficult (or SHOULD find it difficult) to distinguish between antibodies generated from exposure to the live pathogen vs a well-designed vaccine?

Or asked another way, would it be the goal of a well-designed vaccine to elicit an immune response that would generate antibodies that are indistinguishable from those generated by exposure to the actual pathogen? Such that an antibody test would test positive in either case?

Or perhaps more to the point - are there examples of vaccines (prior to 2019) that lead to the creation of antibodies that are not detected by clinical tests for naturally-induced antibodies (where such tests exist) ?

Answer 1

Short answer: no.

Because all vaccines (that I know of) rely on protein or polysaccharide production in some form, whether "natural" (e.g. inactivated virion, subunit vaccines) or "artificial" (purified protein from expressed genes) forms, and the aim is to elicit an immune response that targets the natural pathogen form, so you need to generate an antibody response that covers that form. Vaccines do indeed induce antibodies

Conversely, naturally acquired infections produce antibodies that may not be seen in a vaccine induced response - this is particularly so for vaccines against a single target. For instance, many of the antibodies against SARS-CoV-2 are against the spike protein only, but the natural infection has all the other proteins in the mix, so you get antibodies against things like the Envelope protein and other expressed proteins. If you can detect these antibodies, then you can distinguish between vaccine and naturally acquired immune responses, but not the other way around.

I have however, thought of a mechanism by which a vaccine might induce different immune responses - if the vaccine itself is in a vector that generates an immune response. This is the case for the ChAdOx1 (Astrazeneca) vaccine, where the spike protein is presented on the surface of a non-infectious chimpanzee adenovirus virion. In this case, the adenovirus component could (and presumably does) induce an immune response. However, this is not against the component you are being vaccinated for, rather against the thing carrying the vaccine component.