King Charles III leaves for a state visit to the Vatican on Wednesday, where he will meet Pope Leo XIV and make history as the first head of the Church of England to pray publicly with the pontiff since the schism between the churches 500 years ago.

The visit comes at a delicate time for the British king following new revelations about his brother, Prince Andrew, who is mired in a scandal surrounding late US sex offender Jeffrey Epstein.

Charles and Queen Camilla will meet Leo for the first time since he succeeded the late pope Francis in May.

On Thursday, Charles and Leo will pray together in the first such public religious moment since Henry VIII broke away from the Catholic Church after the then pope refused to annul his marriage to the Spanish princess Catherine of Aragon.

In 1961, the king's mother, the late queen Elizabeth II, became the first British monarch to visit the Holy See since the 16th-century fracture.

The two-day visit will "mark a significant moment in relations between the Catholic Church and Church of England, of which His Majesty is Supreme Governor", Buckingham Palace said.

Thursday's ecumenical service in the Sistine Chapel will be held under the magnificent ceiling adorned with the paintings by Michelangelo. Its main theme will be conservation and protecting the environment, a cause which has been the life work of Charles.

It will bring together Catholic and Anglican traditions, with the choir from the Sistine Chapel being joined by that from Saint George's Chapel, Windsor Castle, one of the residences of the king and queen.

"It is a historic event principally because the king is supreme governor of the Church of England and required by law to be a Protestant," said William Gibson, professor of theology at Oxford Brookes university. "From 1536 to 1914 there were no formal diplomatic relations between the United Kingdom and the Holy See, and the mission was only upgraded to an embassy in 1982."

Charles and Queen Camilla are also set to take part in an ecumenical religious service at the Basilica of Saint Paul Outside the Walls in Rome, part of a symbolic visit underscoring ties between the Anglican and Catholic Churches.

During the Vatican visit, the king will be formally made a "Royal Confrater" of the abbey adjoining the basilica – a gesture Buckingham Palace described as recognising a "spiritual communion" between the two denominations.

A specially designed seat for Charles III will be installed in the basilica and preserved for use by future British monarchs.

The visit coincides with preparations for the Catholic Church's Jubilee Year, held every 25 years, which draws millions of pilgrims to the Vatican.

It also comes a day after the publication of the posthumous memoir by Virginia Giuffre who alleges she was trafficked by Epstein and forced to have sex with the king's younger brother Prince Andrew on three occasions, including twice when she was just 17. Andrew announced on Friday he would relinquish his title as Duke of York, reportedly under pressure from Charles. He had already stepped back from royal duties in 2019.

The 76-year-old king meanwhile continues to receive treatment for cancer, which was publicly disclosed in early 2024. The monarch is no stranger to the Vatican, having visited the Holy See several times in the past.

He and Camilla met privately with pope Francis on April 9, just days before the pontiff's death, during a state visit to Italy. (AFP)