Canadian data show low flu vaccine protection against H3N2

A midseason glimpse of flu vaccine effectiveness (VE) in Canada shows that protection against the H3N2 strain is very low, similar to what Australian scientists reported in the fall, part of what contributed to a tough flu season in in that country.

A team from Canada's Sentinel Practitioner Surveillance Network (SPSN) detailed its findings today in Eurosurveillance. Their study came with a glimmer of good news: more evidence that the influenza B vaccine may provide some cross-lineage protection.

As Australia battled a tough 2017 flu season, led by H3N2, researchers in late October reported interim flu VE at 33% overall, which is low, but protection against H3N2 was even lower, at 10%. Experts warned that if H3N2 dominated the Northern Hemisphere's flu season, the vaccine might not provide much protection.

Over the past few years, H3N2 has posed an extremely complicated challenge for vaccine strain selection and development. H3N2 vaccine viruses grown in eggs acquire adaptive changes that alter antigenicity, and wide genetic diversity in circulating H3N2 viruses makes it tough for experts to select candidate vaccine viruses that are likely to be most protective.

Though H3N2 has been the main driver in the US flu season, which began early and is still rising, Canada saw an unusually early arrival of influenza B, which has circulated alongside H3N2. Parts of Europe and Asia have also reported early and brisk influenza B activity, sometimes edging out H3N2.

Protection similar to Australian findings

The Canadian team used data from medical providers in Alberta, British Columbia, Ontario, and Quebec to gauge the effectiveness of this year's vaccine using patient samples collected from Nov 5, 2017, to Jan 20.

Using a test-negative study design, they found an adjusted overall estimate of 42% (95% confidence interval [CI], 25% to 55%), but adjusted VE against H3N2 was a statistically not significant 17% (95% CI, -14% to 40%), which was less than half the protection offered against the strain by last season's vaccine. When the researchers looked at protection in working-age adults ages 20 to 65—most of the patients in the study—the vaccine's protection against H3N2 was even lower, at 10%, comparable to Australia's estimate and also statistically not significant.

For influenza B, VE was higher, at 55% overall (95% CI, 38% to 68%) but 40% (95% CI, 10% to 60%) in the working age-group. Nearly all of the sequenced influenza B viruses belonged to the Yamagata lineage, which isn't included in Canada's trivalent flu vaccines.

Of flu specimens collected, most of the sequenced H3N2 viruses were part of the 3C.2a genetic clade, and most of those belonged to a single category called subgroup 3. The pattern was similar to other reports from Canada and recent updates from Europe, but different from Canada's last season or Australia's 2017 season, which involved a mix of genetic variants.

The team said the changes in the predominance of H3N2 genetic variants bears close watch, especially ahead of a Feb 19 through 21 meeting of the World Health Organization flu vaccine strain selection committee, which is slated to recommend the strains for the Northern Hemisphere's 2018-19 flu season. The H3N2 strain already picked for the Southern Hemisphere's upcoming flu season is a member of the clade that dominated in parts of the Northern Hemisphere last season.

The findings underscore recommendations made earlier this season that other measures should be used early to protect high-risk groups from flu, the group wrote. Steps include antiviral treatment for suspected flu, regardless of vaccination status or diagnostic test results, and the consideration of antiviral prophylaxis for curbing outbreaks in healthcare facilities.

More hints of flu B cross-protection

The 55% protection the group saw against influenza B came despite the trivalent vaccine lineage mismatch, and roughly 70% of the vaccine doses distributed in SPSN provinces were trivalent, suggesting substantial cross-protection, which the investigators also documented during Canada's previous flu season.

They said the vaccine's protection so far against influenza B is similar to Australia's interim estimate of 57% for its past season, when all of that country's vaccine covered both influenza B lineages.

What do the findings mean?

Danuta Skowronski, MD, the study's lead author, told CIDRAP News that the changes seen with H3N2 aren't characterized as "drift" or "mismatch," which refer to antigenic characterization, done by hemagglutination inhibition assay, which has been challenging for researchers testing flu viruses. Of a small group of H3N2 viruses that can be characterized, most are similar to cell-grown vaccine virus strains, with a greater proportion distinct from the egg-grown vaccine strain.

"So the issue of match/mismatch is complicated by those egg-adaptation mutations," said Skowronski, who is with the British Columbia Centre for Disease Control and the University of British Columbia in Vancouver.

"Bottom line: The VE is low and we have a dominant genetic variant circulating."

So far, it's unclear if Canada's VE findings will look anything like VE patterns in the United States. Though the United States has different flu vaccine formulations, Skowronski noted that most of the country's flu vaccine is still made with egg-based methods. The US Centers for Disease Control and Prevention (CDC) said in its latest FluView report that genetic analysis of H3N2 viruses shows extensive genetic diversity, with many clades and subclades circulating.

US interim flu VE estimates are due out sometime this month.

As for influenza B, Skowronski said researchers haven't given enough attention to the signals that cross-lineage effects are sending about flu immunity, in general. "Those are very important signals," Skowronski said.

Low H3N2 performance remains a puzzle

Ed Belongia, MD, director of the Center for Clinical Epidemiology & Population Health at Marshfield Clinic Research Institute in Marshfield, Wisc., is part of a team that analyzes flu VE in United States. While the Canadian group has good news suggesting cross-lineage protection against influenza B, he said the low VE found for H3N2 is very disappointing, coming in substantially lower than the protection that both the United States and Canada saw against the strain last season.

Given that the vaccine strain is the same, the main question is what's different about vaccine performance this year, Belongia said. "The bottom line is we don't know why this year is different."

He added, however, that there are a few clues. One is the possible impacts of egg-induced adaptations in the vaccine virus, findings that were detailed in a November study. Researchers found that the egg-adapted virus lacks a key glycosylation site on the hemagglutinin protein. "How much of a role that plays, we don't know," he said. "But it's a big issue overall."

Other factors to explore are effects of repeated vaccination and the potential for age-related cohort effects, which involve a process called "antigenic imprinting."

Belongia said the possible contribution of the dominant H3N2 subgroup 3 circulating in Canada this season is interesting, but he noted that Australia had much smaller subgroup 3 numbers and still had similarly low protection against H3N2. "It could be multiple factors," he said. "It remains a puzzle."

Though the long-term goal to better protect against H3N2 and emerging strains points to work toward a universal flu vaccine, he said efforts should also be geared toward shorter-term fixes in the current flu vaccines, with an eye toward nailing down a platform that can give moderately high protection.

Belongia said experts already know there's a problem with egg-based vaccines. And he added that the United States already has licensed vaccines that are not based on eggs. One of the next steps for researchers, he said, is to gather efficacy data on them to enable comparisons needed to guide decisions about investments in new technologies to boost non-egg flu vaccine production systems.

See also:

Feb 1 Eurosurveill report

Oct 26, 2017, CIDRAP News scan "Interim results from Australia put flu vaccine effectiveness at 33%"

CDC FluView report

Nov 8, 2017, CIDRAP News scan "Study: H3N2 mutation in egg-based vaccines lowered efficacy"

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