The accident occurred near Montbeugny, just a short distance from the site of another crash in March that left 12 Portuguese minibus passengers dead.
Today the two Germans' vehicle swerved to the left for an unknown reason and collided head-on with a heavy lorry, an AFP journalist said.
The two crash victims, aged 23 and 28, died instantly. The shocked Spanish lorry driver was taken to hospital nearby.
The Central Europe Atlantic Road (RCEA in its French acronym) sees several accidents each year, many of them deadly.
Their minibus was travelling from Switzerland to Portugal, taking the group home for the Easter holidays.
A local official last month described the motorway, which cuts across the country from east to west, as "the deadliest road in France".