Egg adaptation can reduce seasonal influenza vaccine matching

What's this about?

People disagree about whether growing flu vaccines in eggs can make them less like the flu viruses spreading among people.

What supporters say

• Flu makers often grow vaccine viruses in chicken eggs before they make the shots.
• Some viruses change as they grow in eggs, which can help them grow there.
• Those changes may make the vaccine train the body's defenses for the wrong virus shape.
• The clearest sign appears with the flu type called A(H3N2).

What critics say

• Egg growth is only one of several things that can make flu shots work less well.
• Lab tests show virus changes, but they do not directly show how many people avoid illness.
• Studies sometimes find cell-grown shots work better, but they cannot prove egg growth caused that gap.
• Flu viruses change often, so a poor match can happen for reasons besides egg-grown changes.

The bottom line

Egg growth can sometimes make a flu vaccine match spreading viruses less well, especially A(H3N2). But scientists cannot blame egg growth for every weak flu season.

Egg-based manufacturing can sometimes make seasonal flu vaccines less closely matched to the viruses spreading in the public. The evidence is strongest for the A(H3N2) strain, but researchers caution that egg adaptation is one cause among several of weak vaccine performance.

The case for

Influenza vaccines have long been grown in chicken eggs. But as some flu viruses reproduce in eggs, they can pick up changes that help them grow there—changes that may also make them look less like the viruses infecting people. This is a biologically credible route by which production can reduce the vaccine’s match to circulating strains, especially for A(H3N2) viruses. 1

Laboratory studies show that H3N2 viruses can develop egg-selected mutations that differ from changes seen in cell culture. Features of modern H3N2 viruses, including their sugar-like surface coatings, can affect how well antibodies recognize an egg-adapted vaccine strain. These experiments do not directly measure how well vaccines prevent illness, but they show how egg growth can alter the target that the immune system is trained to recognize.

Clinical evidence points in the same direction, though less consistently. A systematic review and meta-analysis found that egg-adaptive changes can reduce vaccine effectiveness, particularly against H3N2. 3 During the 2012–13 season, researchers linked egg-adaptive H3N2 mutations to antigenic differences from the viruses then circulating, alongside low observed vaccine effectiveness. 2

Studies comparing vaccine types have also sometimes found that cell-based vaccines perform better than egg-based products in adults, children and other groups. That pattern is consistent with the idea that avoiding egg-grown changes may help preserve a closer match to circulating viruses (see Figure 1). But such comparisons cannot by themselves prove why one product performed better.

The case against

The central difficulty is assigning blame. Poor flu-vaccine performance has many causes, and egg adaptation cannot explain every disappointing season—or even necessarily most of the problem in a given season. Flu viruses can evolve after vaccine strains are chosen, leaving any vaccine behind the circulating virus. Immune responses may also be weak or shaped by a person’s past infections and vaccinations.

For H3N2 in particular, studies have pointed to poor immune responses, immune history, vaccine-virus growth properties and problems with laboratory reference viruses as other possible explanations. One analysis concluded that weak immune responses and immune-history effects could account for much of the poor H3N2 performance in 2012. Another found that instability in the viruses used for laboratory testing could distort apparent measures of mismatch or antibody response. 4

Nor does finding an egg-adaptive mutation automatically mean the vaccine will offer less protection. In serology research from 2012–13, scientists found similar antibody levels against both the intended strain and its egg-adapted version, despite detecting egg-related mutations. 5 In other words, a genetic change is not, on its own, proof of a meaningful clinical effect.

The apparently stronger performance of some non-egg vaccines has limits as evidence, too. Most real-world comparisons are observational, meaning the people receiving one vaccine may differ from those receiving another in age, health, healthcare use or other ways. Differences between manufacturers and products, as well as possible sponsorship-related factors, can also complicate results. Randomized trials have mainly measured immune responses, rather than whether vaccines prevent illness over an entire flu season.

The bottom line

The evidence supports the claim with an important qualification: egg-based production can reduce antigenic matching and, in some seasons, lower influenza-vaccine effectiveness. The concern is clearest for particular H3N2 viruses. 13

But egg adaptation is not a universal explanation for low flu-vaccine effectiveness. Its impact varies with the specific mutation, the circulating viral strain, the vaccine formulation and the season. Cell-based and recombinant vaccines can avoid this egg-specific source of change, but they cannot eliminate other problems, including viral drift after strain selection, prior immunity and imperfect immune responses.

Overall, the evidence strongly supports egg adaptation as a real contributing factor. What remains uncertain is how much of any observed gap in vaccine performance can be assigned specifically to egg growth, rather than to the many other forces that shape a flu season.