The breakthrough may lead to a simple blood test that helps doctors identify people unlikely to respond.
Just as chemotherapy works better in some cancer sufferers, the same goes for immunisation.
Now scientists have shown the reason lies in DNA after a study found a number of genes linked to flu vaccination.
Professor Ruth Mongomery said it “offers the possibility of modulating an individual’s immune state before vaccination to improve the resulting antibody response.”
She added: “Although the presence of an inflammatory gene signature, for example, was associated with better antibody responses in young individuals, it was associated with worse responses in older individuals.
“These results point to the prospect of predicting antibody responses before vaccination and provide insights into the biological mechanisms underlying successful vaccination responses.”
The findings published in Science Immunology open the door to using genetic profiles for the flu vaccine.
Prof Mongomery, of Yale University, New Haven, Connecticut, said they shed fresh light on the biological explanation – and will help develop ways to improve treatment.
Alarmingly, current estimates suggest the vaccine is ineffective for up to half of those aged under 65.
In the UK an average of 600 people a year die from complications of flu, but in some years this can rise to over 10,000.
It also leads to hundreds of thousands of GP visits and tens of thousands of hospital stays a year.
Prof Mongomery said although vaccination is the best way to protect against infection, the effectiveness of the flu jab varies widely.
She said: “Despite the overall public health success of influenza vaccination, many individuals fail to induce a substantial antibody response.”
So, to get to the bottom of it, she and her colleagues used data collected from more than 500 participants who provided blood samples before and after being vaccinated.
The analysis identified several gene ‘signatures’, or groups of genes, that were associated with a stronger response to the jab.
This was determined by increases in antibodies that protect against infection.
Flu epidemics can kill thousands or even millions of people.
The 1918 flu epidemic is estimated to have affected half the world’s population, and killed 40 to 50 million people worldwide.
Flu vaccination is available every year on the NHS to help protect adults and children at risk of flu and its complications.