A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine

Abstract

The effectiveness of the annual influenza vaccine has declined in recent years, especially for the H3N2 component, and is a concern for global public health. A major cause for this lack in effectiveness has been attributed to the egg-based vaccine production process. Substitutions on the hemagglutinin glycoprotein (HA) often arise during virus passaging that change its antigenicity and hence vaccine effectiveness. Here, we characterize the effect of a prevalent substitution, L194P, in egg-passaged H3N2 viruses. X-ray structural analysis reveals that this substitution surprisingly increases the mobility of the 190-helix and neighboring regions in antigenic site B, which forms one side of the receptor binding site (RBS) and is immunodominant in recent human H3N2 viruses. Importantly, the L194P substitution decreases binding and neutralization by an RBS-targeted broadly neutralizing antibody by three orders of magnitude and significantly changes the HA antigenicity as measured by binding of human serum antibodies. The receptor binding mode and specificity are also altered to adapt to avian receptors during egg passaging. Overall, these findings help explain the low effectiveness of the seasonal vaccine against H3N2 viruses, and suggest that alternative approaches should be accelerated for producing influenza vaccines as well as isolating clinical isolates.

Assessment of enhanced influenza vaccination finds that FluAd conveys an advantage in mice and older adults

“…Subsequent experiments focused on H3-HAspecific responses as a result of the challenge of antigenic matching for current vaccines and reduced vaccine efficacy. 3,6 Our initial study also found improved responses to enhanced vaccines for H3N2 viruses, 18 and we also observed similar trends for H1-HA-specific responses (Supplementary figures 1 and 5) and influenza B responses with limited reagents (data not shown).…”

“…Adults over 65 years of age are the most susceptible group to complications of influenza infection, account for the majority of influenza‐associated mortality and are widely recommended for annual vaccination . Influenza vaccine effectiveness varies from year to year and can be impacted by antigenic drift, mismatch, pandemic emergence, egg adaptations and age . Standard‐dose inactivated influenza vaccines (S‐IIV) contain 15 µg of haemagglutinin (HA) per strain and are the most widely used vaccine formulation to reduce the burden of seasonal influenza epidemics .…”

Prediction of influenza vaccine effectiveness for the influenza season 2017/18 in the US

“…Recently, lack in effectiveness of influenza vaccine against H3N2 viruses has been attributed to mutation L194P in HA1, which is generated during the egg-based vaccine production process 6 . To test the effect of this mutation on the informational properties of HA1, we included this mutant of the vaccine virus in our analysis.…”

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

“…A common factor over the last several years of low VE against influenza A(H3N2) is that changes to the 62 virus occur during its adaptation to eggs for vaccine production. Studies have suggested that changes 63 required to adapt influenza viruses for growth in eggs may have contributed to low VE in years with 64 influenza A(H3N2) circulation, including 2012-2013, 2016-2017, and this most recent season [5][6][7]. Egg-65 related changes can happen in multiple hemagglutinin epitopes and those egg-adaptation sites of 66 concern have changed since the 2014-2015 season.…”

“…Egg-65 related changes can happen in multiple hemagglutinin epitopes and those egg-adaptation sites of 66 concern have changed since the 2014-2015 season. Specifically, influenza A(H3N2) viruses belonging to 67 the 3C.2a genetic group, which emerged in 2014-2015, acquired a glycosylation site in the 68 hemagglutinin antigenic site B [6][7][8]. This glycosylation site is lost during adaptation to eggs, and, as a 69 result, human and ferret serum raised against egg-adapted A(H3N2) vaccines have shown reduced 70 inhibition of recently circulating viruses [7,9].…”