I resolved this, not sure why it happened in the first place? Any insight would be appreciated so I can prevent this from happening again.
What was happening was the server having an issue was not getting updates from the ePO server and the framework service went from using port 9081 (settings we have on the ePO server for Agent Wake-Up HTTP port) to 8081. I put the FramePkg.exe file from the ePO server to the problem server, after uninstalling the current agent, and everything seemed to work.
Below is an error I saw in the Agent_'server name'_error.log file on the problem server.
[Generate SPIPE package]-> Null signature key
A little odd, as the wakeup port would not be used for an actual update itself.
By reinstalling though, you will have refreshed a lot more besides.
It's more likely the sitelist.xml file was replaced with a default copy somehow that did not contain the correct references to allow updates to occur. A non-managed install of the agent might do that for example.
The right one is bundled in the agent install package generated by the ePO server, so reinstall would have fixed that.
I switched out from the secure to unsecure ports on 4.5 (from possibly use 443 to only use 80) and most of my 4.5 agents didnt switch (which was fun for the firewalled ones) I added a new totally made up http repository to make sure they all got the new sitelist.xml and woke em all up and this worked OK from then.
Worth a try