Friday, November 03, 2017

PLoS Path.: A Structural Explanation For The Low VE Of Recent H3N2 Vaccines


Although the seasonal flu vaccine continues to turn in respectable - if not exactly spectacular - vaccine effectiveness (VE) numbers against influenza B and H1N1, the same cannot be said for its recent performance against the H3N2 virus. 
According to the MMWR, last year in the United States, the vaccine was only about 34% (95% CI = 24%–42%) effective against H3N2.
While growing diversity among circulating H3N2 viruses undoubtedly plays a part (see The Enigmatic, Problematic H3N2 Influenza Virus) - even years when the vaccine virus strain is considered a good antigenic match to circulating viruses - the H3N2 component of the flu vaccine tends to under perform.

Increasingly scientists are looking towards tiny mutations that can arise during the (primarily egg-based) vaccine manufacturing process (see 2014's PLoS One  Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses).
We've a recent study - published in PloS Pathogens - that examines the finished vaccine product using high-resolution  X-ray crystallography and documents tiny mutations that are produced when the virus is passaged through eggs. 
Mutations that change its receptor binding properties, resulting in a lower VE in humans.
First a link and some excerpts from the PLoS study, then some excerpts from a Scripps Research Institute press release.

A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine 
Nicholas C. Wu, Seth J. Zost, Andrew J. Thompson, David Oyen, Corwin M. Nycholat, Ryan McBride, James C. Paulson, Scott E. Hensley, Ian A. Wilson
Published: October 23, 2017


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.

Author summary

Seasonal influenza vaccine does not always confer protection in vaccinated individuals. Vaccine candidates are selected from clinical isolates based on their antigenic properties. It is common to use chicken eggs for culturing clinical isolates and for large-scale production of vaccines.

 However, influenza virus often mutates to adapt to being grown in chicken eggs, which can influence antigenicity and hence vaccine effectiveness. Here, we structurally characterize an egg-adaptive substitution, namely L194P, in H3N2 virus hemagglutinin. Our results reveal that the L194P substitution substantially increases the flexibility of an epitope region that is commonly targeted by antibodies. 

Based on the binding affinity of a broadly neutralizing antibody and a panel of human serum antibodies, we further show that the L194P substitution dramatically changes the HA antigenicity. The change of the receptor-binding mode associated with the L194P substitution provides an explanation for its ability to successfully grow in eggs. Our study describes a mechanism for the low influenza vaccine effectiveness and reaffirms the urgency for replacing the egg-based production of influenza vaccines.

(Continue . . . )

How flu shot manufacturing forces influenza to mutate
Egg-based production causes virus to target bird cells, making vaccine less effective
Date: October 30, 2017
Source:Scripps Research Institute
Summary:The common practice of growing influenza vaccine components in chicken eggs disrupts the major antibody target site on the virus surface, rendering the flu vaccine less effective in humans.
According to a new study from scientists at The Scripps Research Institute (TSRI), the common practice of growing influenza vaccine components in chicken eggs disrupts the major antibody target site on the virus surface, rendering the flu vaccine less effective in humans.
"Now we can explain -- at an atomic level -- why egg-based vaccine production is causing problems," said TSRI Research Associate Nicholas Wu, Ph.D., first author of the study, published recently in the journal PLOS Pathogens.
 (Continue . . . )

Egg-based manufacturing of vaccines is 70-year-old technology, and while cheap, has long been considered the weak link in the vaccine production cycle.  It requires millions of eggs, and about 6 months, to produce a new vaccine - assuming nothing goes wrong.
Newer cell-based manufacturing may reduce these problems, but for now egg-based manufacturing makes up the bulk of vaccine production.
In 2012, in CIDRAP: The Need For `Game Changing’ Flu Vaccines, we looked at major report – serving as a clarion call for a revolution in vaccine technology - that is as relevant today as the day it was published.

Since reports like this one tend to make a big splash, and then are all too quickly forgotten, today seems a good day to revisit that study.

The Compelling Need for Game-Changing Influenza Vaccines

An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future
Michael T. Osterholm, PhD, MPH, Nicholas S. Kelley, PhD, Jill M. Manske, PhD, MPH, Katie S. Ballering, PhD, Tabitha R. Leighton, MPH, Kristine A. Moore, MD, MPH

For those not ready to commit to reading a 160-page report, there is a 12-page Executive summary available.
While some progress has been made (adjuvanted, cell-based, and high-dose vaccines are now available), seasonal flu vaccines still pale in effectiveness compared to other types of vaccines. 
Despite their current shortcomings, some protection beats no protection at all, and so I get the flu shot every year and urge others to do so as well.  For more on all of this, you may wish to revisit:

Eurosurveillance: End Of Season Flu Vaccine Effectiveness - UK 2016-2017 

More Evidence Flu Shots May Improve Outcomes In Critical Patients

Eurosurveillance: Low H3N2 Vaccine Effectiveness In Australia's 2017 Flu Season


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