At least 19 people have died from the disease, which is usually spread through contaminated drinking water, in the country's flood-hit northern Fangak County since April, the aid group said in a statement.
But the death toll could be higher as years of flooding have turned the region's villages into islands, forcing resident to use canoes to travel and cutting them off from the nearest hospital, it added.
The vaccination campaign, which began on December 11, "is the first to be conducted during the acute stages of an active Hepatitis E outbreak anywhere in the world," said the group, which is known by its French initials MSF.
By June the group hopes to fully vaccinate 12,776 women and girls aged 16-45 in these villages, which have also been affected by malaria and malnutrition.
Women are most at risk from hepatitis E, which has a fatality rate "as high as 40 percent for pregnant women," MSF said.
More than 500 people have been treated for the disease at the hospital in the town of Old Fangak since April.
Hepatitis E is a liver disease caused by a virus transmitted through poor sanitation that affects 20 million people globally a year, according to the World Health Organisation.
Symptoms include fever, vomiting and jaundice, and in rare cases liver failure.
"There is no cure for hepatitis E and sadly, 70,000 people die from the disease each year," said Mamman Mustapha, MSF's head of mission in South Sudan.
The only WHO-authorised hepatitis E vaccine was developed in 2012 by the Chinese firm Xiamen Innovax Biotech.
But the company does not produce large quantities of the vaccine and doses can be expensive, MSF said.
The first mass vaccination campaign using the jab was carried out in South Sudan's Bentiu displacement camp in 2022, inoculating more than 25,000 people, it added.
The aid group called for more vaccine doses to be produced, and for local health and humanitarian organisation to improve the water and sanitation conditions in the region.
PARIS - Doctors Without Borders announced Wednesday that it had begun a mass vaccination campaign against hepatitis E in South Sudan, where an outbreak of the deadly disease is threatening pregnant women in particular.
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