It happened at around 3:45 pm Wednesday on Highway 43 near Davis Avenue, east of Kingsburg.
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The California Highway Patrol says a black Chevy Tahoe SUV was driving south on the highway when it crossed over the centerline and collided with a big rig hauling sand that was traveling north.
The adult female in the SUV had significant injuries, while an adult male and a three-year-old boy in the SUV had minor injuries.
A two-year-old boy in the SUV was killed.
The driver of the semi-truck was not injured.
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Highway 43 was expected to remain closed until at least 7 pm while the California Highway Patrol investigates the crash.
Alcohol and drugs do not appear to be a factor in the collision.