Poor immune responses, not adaptions in egg-grown vaccines, appear to have been the cause of low influenza vaccine effectiveness during a past flu season, a new study reports.

An article in Clinical Infectious Diseases recounts how, in 2012-13, the H3N2 component of the flu vaccine was effective in just 39% of those immunized, and public health officials posited that adaptations in egg-grown vaccines were the problem.

University of Chicago–led researchers point out that problems with how the vaccine is designed and produced are often blamed for low effectiveness, whether the flu strains are determined to be a poor match or whether the vaccines mutate while being grown in eggs.

“Egg adaptations have variable effects,” explained lead author Sarah Cobey, PhD, assistant professor of ecology and evolution at the University of Chicago and lead author of the study. “Sometimes they matter and sometimes they don't, but what seems to make the most difference is immune history.”

The researchers suggest the key is something called original antigenic sin. Their study determined that antibodies produced from someone’s first experience with influenza—whether from vaccination or infection—usually takes precedence over any generated by later efforts at immunization. The result? Even if the vaccine is a good match for a given year, an individual’s immune response could be less protective if they have a history with the flu. Complicating matters, the authors note, is that the vaccine could be inducing a weak immune response in many who receive it.

To determine that, the study team evaluated whether vaccinated and unvaccinated individuals in 2012-2013 were infected by different viral strains and also assessing the serologic responses to IVR-165, A/Victoria/361/2011, and 3C.2 and 3C.3 strains in an adult cohort before and after vaccination. Results failed to indicate any significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. The researchers did determine, however, that vaccination increased titers to A/Victoria/361/2011 and 3C.2 and 3C.3 representative strains as much as to IVR-165.

“These results are consistent with the hypothesis that vaccination boosted cross-reactive immune responses instead of specific responses against unique vaccine epitopes. Only ~1/3 of the cohort achieved a ≥4-fold increase in titer,” study authors emphasize, adding, “In contrast to analyses based on ferret studies, low H3N2 VE in 2012-2013 in adults does not appear to be due to egg-adaptation of the vaccine strain. Instead, low VE might have been caused by low vaccine immunogenicity in a subset of the population.”

“We see that both vaccinated and unvaccinated people were infected with similar flu viruses and that the vaccine didn’t elicit a strong immune response from most people in our study,” said co-author Yonatan Grad, MD, PhD, assistant professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health.

Grad described the situation this way: “Imagine influenza viruses are like different makes and models of cars. The ferrets, which hadn’t seen influenza before, learned to tell the difference between closely related strains-like telling the difference between a Honda Civic and a Toyota Camry. But people didn’t distinguish between them and instead just saw cars.”

The study team did not suggest that egg adaptions weren’t an issue. In fact, Cobey was involved in the work of other researchers who stated that was the likely cause of issues in 2016-17, when H3N2 also dominated.