Mako Vunipola will miss England’s entire autumn Test series with a calf strain, deepening boss Eddie Jones’ front-row injury crisis.

Saracens’ loosehead prop will be sidelined for six weeks, with lock Nick Isiekwe also ruled out for two months due to an ankle concern – taking England’s contingent already confirmed to miss the autumn series to 16 players.

Mako Vunipola becomes England’s fourth loosehead missing ahead of the autumn: Joe Marler has retired from Test rugby, while Leicester’s Ellis Genge, Bath’s Beno Obano and Wasps’ Matt Mullan are all sidelined with long-term knee trouble.

“Mako’s got a calf injury, so it looks like it’s going to be around six weeks,” said Saracens rugby director Mark McCall.

“It’s a tear in his calf, it doesn’t require surgery.

“Nick (Isiekwe) will be around eight weeks, it’s a syndesmosis injury of his ankle.

“That doesn’t require surgery either, and it will be eight weeks.”

Head coach Jones will therefore have to hand someone a full debut in the first autumn Test, against South Africa at Twickenham on Saturday, November 3.

Exeter Chiefs’ Alec Hepburn has one cap as a replacement, while his club mate Ben Moon and Gloucester’s Val Rapava Ruskin will now be England’s other main options at loosehead prop.

Nathan Hughes could yet become another casualty for England’s autumn, with the Wasps number eight facing a reconvened disciplinary hearing on Wednesday night.

But Mako Vunipola and Isiekwe join Genge, Obano, Mullan, Joe Launchbury, Jonny Hill, Billy Vunipola, Sam Simmonds, Jack Willis and Chris Robshaw as England’s sidelined forwards.

Dan Robson, Jonathan Joseph, Anthony Watson and Marland Yarde are all missing from the backline, with Ben Te’o still a doubt despite working his way back to fitness.

Saracens boss McCall was left to count the cost of Sunday’s 13-3 Champions Cup defeat at Glasgow, where both Vunipola brothers and Isiekwe picked up their latest injury setbacks.

Billy Vunipola broke his left arm – his third arm fracture of 2018 – at Scotstoun, while Mako Vunipola and Isiekwe also succumbed to injury north of the border.

McCall insists the injury issues are just pure bad luck however.

“It is what it is, isn’t it?” said McCall.

“Mako’s is just a soft tissue injury.

“Nick just goes for a ball gets into an unfortunate position.”

Now England must take on South Africa, New Zealand, Japan and Australia next month with without yet more frontline stars.

Jones will name his autumn squad on Thursday morning, where he will chart the way forward without a sizeable sidelined cohort.

Danny Cipriani maintains hope of an England recall.

The 30-year-old was left out of the latest England training group last month.

The fly-half scored 14 points in Gloucester’s European Champions Cup win over Castres last Sunday, in front of Jones.

Cipriani told Channel 4: “I think there’s a chance. ‘There’s always a chance’, as Jim Carrey said.

“I’ve just got to keep doing what I’m doing. If I get picked then it will be amazing. I will go and do everything I can to do the right thing on and off the field, get ready for it.

“Your ego might take a hit when you don’t get picked, but, as a person, does it change you? It doesn’t, you’ve just got to keep going.

I’ve still got a target to go and get and there’s no harm when you can see the light at the end of the tunnel, whether you’re reach it or not. But at least you’re going towards something.”