Barring Antibody-dependent enhancement (ADE), how else can vaccines enhance the infection?

Question

The link to the 2007 article below was broken for me. I Googled and read it on NCBI.

Decades ago, vaccines developed against another coronavirus, feline infectious peritonitis virus, increased cats’ risk of developing the disease caused by the virus (T. Takano et al. J. Vet. Med. Sci. 81, 911–915; 2019). Similar phenomena have been seen in animal studies for other viruses, including the coronavirus that causes SARS (Y. W. Kam et al. Vaccine 25, 729–740; 2007).

At p 737 on the right column, the authors "could exclude this mechanism of enhancement as sera from triSpike vaccinated mice did neutralize, rather than enhance, virus infection on VeroE6 cells." So I similarly exclude ADE for this question. But in the last para. they wrote

Interestingly, we observed the enhancement phenotype only in human B cell lines but not in mouse macrophages despite the presence of FcγRII. Reasons for this are unclear, but the respective role of activating and inhibiting human FcγRII which have identical extracellular

p. 738

but heterologous intracellular domains and signaling capacities might play a role [63].

Answer 1

Vaccines are now well-tested to make sure that they don't do make infection worse, but there are many ways they COULD.

Two early formalin-inactivated vaccines (RSV and measles) both had this effect. See this Reddit post to understand the mechanisms.

Theoretically, a poorly-designed vaccine could worsen viral infections in three ways:

1. by biasing the adaptive immune response in the wrong direction that makes it harder to effectively respond to the actual virus. This might be by priming the wrong type of response, e.g. producing a strongly biased Th2 response when a Th1 is required); creating the right response but to the wrong epitopes, in a way that subsequent exposures can't overcome - "original antigenic sin"; or by inducing T/B cell anergy or tolerance to the virus in question.

2. immunopathology. For many viruses, the immune system's attempts to kill the virus, not the virus itself's direct cytolytic effects, damage the host. E,g, Hepatitis C has 3 broad outcomes to a natural infection: about 20% of people create an early, strong, multi-specific CD4/8 response that clears the virus. The rest develop chronic infection. In most people with chronic infection, the immune response damages little - viral loads can be extremely high but liver fibrosis is minimal. But in \~10-20%, there is a strong immune response: chronic inflammation, infiltration of lymphocytes, and constant direct killing of virally-infected hepatocytes by CTLs leads to deposition of scar tissue and, eventually, cirrhosis. So if you created a vaccine that failed to clear the virus and instead generated a pro-inflammatory, pro-fibrotic immune response, it would be a disaster.

3. Increased target cells. This was a concern with one of the experimental HIV vaccines. It increased the number of CD4+ cells permissive to HIV infection in the female genital tract (and the rectum, but I don't remember), thus giving the virus more target cells to infect (there was also an experimental HPV vaccine that was feared to do the same). Those vaccinated thus had increased risk of infection.