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The Western Freeway has been closed in both directions between Bacchus Marsh and Ballan as a result of the multi-vehicle crash at Myrniong just before 4pm, around 58 kilometres west of Melbourne.
Ambulance Victoria said two people had been taken to Ballarat Base Hospital from the Myrniong crash, while paramedics were treating at least 18 other patients at the scene.
There were no suspected injuries involved in the West Gate collision, Victoria Police confirmed.
Police are blaming the collisions on heavy fog in the area and said there were no serious injuries at this stage.
Motorists heading towards Ballarat will be diverted off the freeway at Bacchus Marsh where they will need to take a lengthy detour using Geelong-Bacchus Marsh Road into Geelong, then Geelong-Ballan Road.
Those heading towards Melbourne will be diverted off the freeway at Greendale-Myrniong Road to take the Old Western Highway and Pentland Hills Road.
For drivers leaving Melbourne, wider detours should be considered including the Princes Freeway to Geelong then the Midland Highway to Ballarat.
A spokesperson from Vic Roads urged motorists to slow down.
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“There are reports of extensive fog covering parts of the Western Freeway,” they said.
“Motorists should slow down, drive to the conditions and have their headlights on to be better seen.”
All drivers bound for Geelong are being directed onto a single lane at the Grieve Parade exit, which is causing delays of more than 90 minutes.
Delays are extended back to the Domain tunnel and are continuing to build.
Motorists are being urged to exit the West Gate Freeway earlier at Williamstown Road or Millers Road, and detouring through Altona North of Brooklyn, and those not yet on the freeway should seek an alternative route such as Footscray or Dynon roads.
Around 25 passengers were evacuated from a V/Line train after it slammed into a truck, killing the truck driver on impact.
There continues to be major delays on the Geelong and Warrnambool lines, with emergency services still at the scene.
A spokesperson from V/Line said trains would continue to operate between Southern Cross and Lara, with coaches to transport passengers between Lara and Waurn Ponds.