Why does the HPV vaccine not work on already infected people?

Question

With my limited knowledge, I understand that the vaccine works by inserting fake HPV-like material in the body, thus inducing the immune system to build up defenses against it, so when the body is exposed to real HPV on the wild the immune system will be able to handle it.

That makes sense, however, why can't the body still build up the defenses when there was already an exposure? Specially when the HPV virus is "dormant" and undetectable.

EDIT: After the discussion with @Bob in the comments section below, the hypothesis is:

In an infected person whose immune system was able to clear the acute infection, the virus (single infected cells) is constantly trying to enter lytic cycle again, only to be defeated by the immune system (because one infected cell leaving dormant state alone might not be effective); and then when the immune system is compromised for some reason, the virus is successful into entering lytic cycle and then there is a new clinical infection.

If this is all truth, then the answer to the question is that the vaccine does "work" in the sense that the body still reacts correctly (by responding to the antigen) to it, but it is, in practice, useless because: 1) when the virus is dormant there isn't anything for the immune system to do; 2) when the virus strikes, the immune system was already exposed to it anyway, so it is generally able to fight and there is no need for the vaccine; 3) the infection will get clinical again only when the immune system is, for some reason, defective.

The whole point of the vaccine is to never let the virus infect many (or any?) cell in order to avoid this situation where it is always trying to come back - and will do, when the immune system can't fight it off for some reason.

Please, if some specialist can analyze and comment on that it will be awesome.

More questions around it:

1. Is there the possibility that, while in this "dormant/attack" cycle, every single infected cell is defeated over the course of time, meaning an actual "cure"?

2. How does the cell replication process impacts the 1) hypothesis? (Maybe it is not possible for the immune system to achieve a natural cure because the virus keeps constantly replicating.)

3. How "much virus" would be needed for a successful strike in a compromised immune system (and how much compromised that system would have to be to fail)?

4. If the virus acts locally, is it possible for the vaccine to help other still-not-infected sites? In other words: is the natural immune response from the first infection in, say, the anus, worth anything for a subsequent infection in, for example, the oropharynx?

Answer 1

This is an excellent question, and it is actually being studied -- but for a different reason than your question suggests. HPV is a bit unique because there is some data showing that infected individuals can become "reinfected" with the same virus type, causing reactivation of the dormant/latent virus that they are already infected with. So the question in this case is whether administering an HPV vaccine to an already infected individual can help prevent (or minimize) reactivation of the latent virus.

Here's a journal article explaining some of this research. Please note that it is not standard medical practice to give HPV vaccine to already infected individuals. This work is still in the research phase, and is aimed at minimizing viral reinfection and reactivation: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006803/

Simply put, a vaccine only works to prevent infection with a specific virus. It is rarely effective in treating a virus once a person has become infected. The reason for this has to do with how the immune system responds to its first encounter and subsequent encounters with a particular virus:

When the body encounters a specific virus for the first time, the immune system mounts a "primary" immune response specific to that virus. A primary immune response triggers the body to produce virus-specific immune cells that can generate antibodies against that virus. The body continues to make these immune cells in small quantities even after the virus is eliminated.

If the same virus is encountered again later, these cells will proliferate and immediately start producing antibodies against the virus. Thus, the body can mount a much faster and stronger "secondary" immune response. This prevents the viral load from reaching levels that produce physical symptoms, so the person does not become sick (or at most they may have milder symptoms), and the immune system is to able eliminate the virus more quickly.

The purpose of a vaccine is to trigger a primary immune response. With a vaccine, the body is exposed to a weakened form of the virus, and a primary immune response is triggered without the individual becoming sick. When the individual encounters the real virus, the body immediately mounts a secondary immune response, which fights off the virus much more efficiently and quickly, and the person typically has no physical symptoms.

Here's a more in-depth explanation on the difference between a "primary" and "secondary" immune response. Most cell biology textbooks (and all immunology textbooks) will have an explanation of this as well. This is an important concept in understanding how vaccines work: http://www.microbiologynotes.com/differences-between-primary-and-secondary-immune-response/

If a non-vaccinated person is infected with a virus, administering a vaccine generally has no effect. At that point the body is already mounting a primary immune response, so a vaccine would serve no purpose. Because a primary immune response is slower than a secondary response, when a non-vaccinated person gets infected the viral load is able to increase more rapidly than it would in a vaccinated individual, resulting in the physical symptoms typical for that particular virus.

What makes "chronic" viruses such as HPV and Herpes virus (including chicken pox) harder to eliminate completely is that these viruses enter a dormant/latent (lysogenic) phase. At that point they become "invisible" to the immune system. Even if the person is not visibly sick, they are still infected with the virus. If/when the active (lytic) phase is triggered, the viral load increases rapidly -- more rapidly than if it were a new viral infection. The body still mounts a secondary immune response, but typically this will not completely eradicate the virus. As long as any amount of the virus is in the lysogenic phase, it remains "invisible" to the immune system.

With some viruses (e.g., chicken pox virus, which causes shingles) if a vaccine is administered during the latent phase, this can help somewhat with making symptoms milder if/when the lytic stage is ever triggered. But this doesn't work for all viruses.

If a targeted antiviral medication is available (e.g., Tamiflu for influenza; Harvoni for Hepatitis C) this can slow down the proliferation of the virus, allowing the immune system to "catch up" and eliminate the virus. Antiviral medications aren't vaccines. They are designed to directly target the virus and interfere with a biochemical activity that the virus needs in order to proliferate.

Currently there is no antiviral medication available for HPV, although a few drugs are being researched. One drug in particular (ranpirnase) looks promising, but it is still in early clinical trials.

Answer 2

I believe the following paper discussing the lifecycle of HPV is of use for understanding at least some of the aspects of your question: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394500/

Specifically:

Viruses like HPV have the capacity to form virions and become transmissible at some point in their natural lifecycles, but within tumors these infections are generally latent so that productive virus replication (also known as lytic replication) is either diminished or absent. Viral latency serves as an immune evasion strategy allowing the virus to hide from the immune system by turning off unnecessary viral proteins that might be sensed by cell mediated immune recognition. The virus persists as a naked nucleic acid, often as a plasmid or episome, which relies on host cell machinery to replicate whenever the cell divides. Viral latency should not be mistaken with clinical latency, which means asymptomatic infection (14).

The most favorable explanation for the connection between virus latency and tumorigenesis is that productively replicating viruses initiate cell death, the known cytopathic effect (CPE). Virus-induced CPE can be harnessed to kill cancer cells in viral oncolytic therapies, illustrating the anticancer activity of active lytic viral replication. Although CPE is often thought of as a virus-induced event, it is in fact a stereotypical and nonspecific innate immune response of cells to infection by many types of viruses. When latent viruses switch to producing virions, virus replication generates pathogen- associated molecular patterns from partially synthesized viral chromosomes, double-stranded RNAs and empty capsids that trigger cellular DNA damage responses and innate immune signalling. For some viruses, lytic replication generates a linear viral chromosome that can be recognized as a DNA fragment unless either the DNA ends are structurally hidden from DNA damage response sensors by encapsidation or these sensors are inactivated (14).

I think this addresses some relevant aspects of your question, namely:

why can't the body still build up the defenses when there was already an exposure?

It can and already has, see my answers to later questions. But it doesn't work on the already present viral infections because:

1. Is there the possibility that, while in this "dormant/attack" cycle, every single infected cell is defeated over the course of time, meaning an actual "cure"?

Not really, since the immune system cannot 'reach' or 'see' the HPV infected cells and thus isn't attacking them until they enter the reproductive phase.

3. How "much virus" would be needed for a successful strike in a compromised immune system (and how much compromised that system would have to be to fail)?

There probably won't ever be an exact number here but the paper I linked above does list some (obviously approximate) numbers regarding HPV activity:

After infection of wound basal cells, it is thought that there is a round of viral DNA replication that appears to be independent of the cell cycle and amplifies the viral copy number to around 50 to 100 copies per cell. The infected cell leaves then this primitive compartment and enters the transit amplifying proliferative compartment of the epithelium, where there is a phase of plasmid or episomal maintenance when the viral copy number remains constant and viral gene expression is minimal. In this phase of the viral life cycle of the high-risk HPVs, the expression of the potent oncogenes E6 and E7 is under strict control, and E6 and E7 transcripts of high-risk HPV types are hardly detectable in the proliferating compartment of the epithelium (10). When the infected keratinocyte enters the differentiating compartment, in the stratum spinosum exiting the cell cycle, then there is an extended upregulation of viral gene expression and viral DNA replication, with amplification of the viral copy number to many thousands of copies per cell, gross expression of the E6 and E7 early genes, and expression of late genes from the late promoter, leading finally to HPV formation

Lastly, you asked:

4. If the virus acts locally, is it possible for the vaccine to help other still-not-infected sites? In other words: is the natural immune response from the first infection in, say, the anus, worth anything for a subsequent infection in, for example, the oropharynx?

The answer to this, I believe, is that if you are speaking of an HPV vaccine of the same strain then it would likely not be useful, since your body's immune system would already recognize the same strain that it already has been fighting off, also in a different location. However, HPV has a couple of different strains and a vaccine for those might help with infections in different locations by different strains. Considering that vaccinations like Gardasil actually cover a lot more than 1 type of HPV, vaccination might still be relevant.

For a source that HPV vaccines cover more than 1 strain, see: https://www.cancer.gov/types/cervical/research/gardasil9-prevents-more-HPV-types and https://www.ncbi.nlm.nih.gov/pubmed/25693011

For a semi-source that already infected people might benefit from vaccination, see: https://www.cancer.gov/news-events/cancer-currents-blog/2015/hpvvaccine-multisite (note that this is from what I can tell pre-publication research presented at a conference and so it all seems quite preliminary).

I also found this paper to be informative on the topic of HPV and the immune system response to it, but it isn't open access so I cannot guarantee that you'll be able to read it. For the sake of completion, I'll still link it: http://dx.doi.org/10.1016/j.ygyno.2013.08.025