Tuesday, November 07, 2017

PNAS: Egg-Passaged Flu Vaccine Antibodies Poorly Neutralize Recent H3N2 Viruses



While there are newer manufacturing techniques (cell-based & recombinant) being phased in, currently most flu vaccines are produced using the 70 year-old process of taking the selected Candidate Vaccine Virus (CVV) and injecting it into fertilized hen's eggs, and then allowing the virus to replicate for a number of days.
The virus-laden fluid is then harvested from the eggs, and (for flu shots) the viruses are then inactivated (killed), and virus antigen is purified. 
While this method has worked moderately well over the past 7 decades it suffers from a number of limitations; it requires a large quantity of eggs, some (particularly novel) flu viruses have been shown to replicate poorly in eggs, and this manufacturing process takes considerably longer than the newer cell-based or recombinant technologies.

Over the past couple of years, a new problem with egg-based vaccines has emerged, specifically with H3N2 viruses. Tiny changes (mutations) can occur which appear to alter how the vaccine recognizes (and protects against) the flu strain it was created from.

While first documented back in 2014's PLoS One study  Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses, the impact of low Vaccine Effectiveness (VE) has increased markedly over the past 12 months.
According to the MMWR, last year in the United States, the vaccine was only about 34% (95% CI = 24%–42%) effective against H3N2. 
Over the past few months we've seen severe outbreaks of H3N2 hit both Hong Kong and Australia, and over the past month we've reviewed a series of reports on very low VEs from Europe last winter, and from Australia's flu season which just ended.
Eurosurveillance: End Of Season Flu Vaccine Effectiveness - UK 2016-2017
Eurosurveillance: Low H3N2 Vaccine Effectiveness In Australia's 2017 Flu Season

Eurosurveillance: Low 2016/17 Vaccine Effectiveness (VE) Among Elderly Hospitalized H3N2 Cases

ECDC: H3N2 Flu Vaccine Component Likely `Suboptimal'

Last week, in PLoS Path.: A Structural Explanation For The Low VE Of Recent H3N2 Vaccines, we looked at a study from the Scripps Research Institute that examined the egg manufactured vaccine using high-resolution X-ray crystallography and documented tiny mutations that changed its receptor binding properties.
Meaning that even though the Candidate Vaccine Virus used was considered a good match to circulating H3N2 virus strains, the finished vaccine product wasn't. 
We've another study, published yesterday in PNAS, which offers further evidence of how these mutations which can appear during the manufacturing process can decrease the finished vaccine's effectiveness.
Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains

Seth J. Zosta, Kaela Parkhousea, Megan E. Guminaa, Kangchon Kimb, Sebastian Diaz Pereza, Patrick C. Wilsonc, John J. Treanord, Andrea J. Sante, Sarah Cobeyb, and Scott E. Hensleya,1

Author Affiliations

    Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved October 12, 2017 (received for review July 11, 2017)   


The majority of influenza vaccine antigens are prepared in chicken eggs. Human vaccine strains grown in eggs often possess adaptive mutations that increase viral attachment to chicken cells. Most of these adaptive mutations are in the hemagglutinin protein, which functions as a viral attachment factor.
Here, we identify a hemagglutinin mutation in the current egg-adapted H3N2 vaccine strain that alters antigenicity. We show that ferrets and humans exposed to the current egg-adapted H3N2 vaccine strain produce antibodies that poorly neutralize H3N2 viruses that circulated during the 2016–2017 influenza season.
These studies highlight the challenges associated with producing influenza vaccine antigens in eggs, while offering a potential explanation of why there was only moderate vaccine effectiveness during the 2016–2017 influenza season.


H3N2 viruses continuously acquire mutations in the hemagglutinin (HA) glycoprotein that abrogate binding of human antibodies. During the 2014–2015 influenza season, clade 3C.2a H3N2 viruses possessing a new predicted glycosylation site in antigenic site B of HA emerged, and these viruses remain prevalent today. The 2016–2017 seasonal influenza vaccine was updated to include a clade 3C.2a H3N2 strain; however, the egg-adapted version of this viral strain lacks the new putative glycosylation site.
Here, we biochemically demonstrate that the HA antigenic site B of circulating clade 3C.2a viruses is glycosylated. We show that antibodies elicited in ferrets and humans exposed to the egg-adapted 2016–2017 H3N2 vaccine strain poorly neutralize a glycosylated clade 3C.2a H3N2 virus. Importantly, antibodies elicited in ferrets infected with the current circulating H3N2 viral strain (that possesses the glycosylation site) and humans vaccinated with baculovirus-expressed H3 antigens (that possess the glycosylation site motif) were able to efficiently recognize a glycosylated clade 3C.2a H3N2 virus.
We propose that differences in glycosylation between H3N2 egg-adapted vaccines and circulating strains likely contributed to reduced vaccine effectiveness during the 2016–2017 influenza season. Furthermore, our data suggest that influenza virus antigens prepared via systems not reliant on egg adaptations are more likely to elicit protective antibody responses that are not affected by glycosylation of antigenic site B of H3N2 HA.
        (Continue . . . )

While this current problem doesn't appear to affect the H1N1 and Influenza B components of the vaccine, H3N2 dominant seasons are often the most severe, particularly for those over 65. And right now H3N2 looks to be on track for a return engagement, although that could change in the months ahead.

In 2012, in CIDRAP: The Need For `Game Changing’ Flu Vaccines, we looked at major report – essentially a clarion call for a revolution in vaccine technology - that is as relevant today as the day it was published.
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 we've seen some progress made on the influenza vaccine front (adjuvanted, cell-based, and high-dose vaccines for example), flu vaccines still pale in effectiveness compared to other types of vaccines, and the antiquated egg-based vaccine manufacturing process remains a serious Achilles's heel. 
Despite an expected `sub-optimal' performance against H3N2 this winter, the flu vaccine is still worth getting as it provides moderately good protection against H1N1 and Influenza B, and there is Evidence Flu Shots May Improve Outcomes In Critical Patients, even when it doesn't prevent infection.
Getting the flu shot - along with practicing good flu hygiene (covering your coughs, washing/sanitizing your hands, staying home when you are sick, etc.) - still remain the best steps you can take to stay healthy during what may turn out to be a particularly difficult flu season ahead.

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