December 10, 2019
4 min read

‘Worthwhile to consider’: Does the world need a pentavalent flu vaccine?

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Brendan Flannery, PhD 
Brendan Flannery
Robert L. Atmar, MD 
Robert L. Atmar

Study findings showed that last season’s influenza vaccine “offered no substantial protection” against H3N2 viruses that moved through the United States late in the season, highlighting the ongoing challenge of producing a vaccine that works against this influenza A subtype and leading two experts to wonder if an additional H3N2 strain should be added to the seasonal vaccine.

The emergence of a drifted H3N2 variant in the second half of the season prompted WHO to postpone choosing an H3N2 virus for the Northern Hemisphere’s 2019-2020 influenza vaccines, which ultimately led to a delay in some influenza vaccine shipments in the U.S.

It was the third time since 2000 that a vaccine strain selection was postponed so that more data could be collected to choose a more appropriate strain, according to Brendan Flannery, PhD, an epidemiologist in the CDC's Influenza Division, and colleagues. The H3N2 component has been changed 12 times in the same period — twice as often as the H1N1 component, they reported.

Late-season H3N2 surge

Flannery and colleagues used data from U.S. virologic surveillance and the Flu Vaccine Effectiveness (VE) Network to evaluate the distribution of influenza viruses in ambulatory patients aged 6 months or older with acute respiratory illness to determine if circulation of the drifted H3N2 viruses — part of clade 3C.3a — resulted in decreased vaccine effectiveness.

Andrew Pavia, MD
Andrew Pavia

According to the researchers, among 2,763 patients in the VE Network, 48% were infected with H1N1 viruses and 49% with H3N2 viruses. H1N1 viruses caused most illnesses early on, and H3N2 viruses predominated during the second half of the longest influenza season in the U.S. in 10 years. Most H3N2 viruses differed antigenically from the vaccine component.

Vaccine effectiveness was 44% against H1N1 (95% CI, 37%-51%), 9% against H3N2 overall (95% CI, –4% to 20%), and 5% against H3N2 clade 3C.3a viruses (95% CI, –10 to 19%).

“While influenza vaccination provided protection against illness due to A(H1N1) viruses, vaccination offered no substantial protection against the antigenically different H3N2 viruses,” Flannery told Healio.

He said vaccination offered some protection against H3N2 viruses that were more similar to the vaccine component, although these accounted for less than 10% of illnesses.

A pentavalent vaccine?

In an accompanying commentary, Robert L. Atmar, MD, and Wendy A. Keitel, MD, of Baylor College of Medicine, noted that the factors affecting vaccine effectiveness can be divided into three areas — virus, host and vaccine. Of these, they wrote, the only modifiable group is vaccine.


“Influenza vaccine is effective at preventing influenza illness, but protection against H3N2 viruses remains a challenge compared to that achieved for H1N1 and B viruses,” Atmar told Healio.

In their commentary, Atmar and Keitel suggest adding a second H3N2 strain to the seasonal influenza vaccine, “an approach taken in some veterinary vaccines,” Atmar said.

Atmar noted that a second influenza B component was added to the seasonal vaccine to make it quadrivalent based upon the experience that the lineage of the predominant circulating B viruses was different than that in the trivalent vaccine about 50% of the time.

“That said, there are significant logistical issues that need to be considered, including the challenges that manufacturers would face producing a pentavalent vaccine,” he said. “We don’t know that this approach will improve our ability to select strains from clades of H3N2 viruses that subsequently circulate, but we thought it was worthwhile to consider.”

Developing a seasonal vaccine that provides longer lasting and wider protection has long been a goal of researchers.

“We agree with the authors that more broadly protective influenza vaccines are needed to provide protection against influenza when circulating viruses change,” Flannery said of the commentary. “If antigenically divergent H3N2 viruses continue to co-circulate and evolve separately, inclusion of H3N2 viruses representative of these different groups may be needed to improve protection until more generally broadly protective vaccines are available. However, immunogenicity of vaccines containing two H3N2 components would need to be tested.”

A problem of production

Andrew Pavia, MD , chief of the division of pediatric infectious diseases at the University of Utah and a spokesman for the Infectious Diseases Society of America, called the suggestion of adding another H3N2 strain “unrealistic.”

“What happened with the season in question is that during the middle of the season, a new clade of H3N2 started to move through,” he told Healio. “In years where there is a shift in H3N2, we don’t really have the information in time for vaccine design with our current production standards. We begin vaccine discussions in February and March, the FDA makes the recommendations for what goes into the winter’s flu vaccine, and with that time, you would not be able to recognize that sort of problem.”

Pavia suggested solving a different problem with vaccines — the production.

“The big problem is not how many strains of H3N2 we put into the vaccine, it’s the production itself. As long as we have egg-based systems that have this long lead time, the problem is not going to be solvable,” he said.

“We are getting close to being able to move away from egg-based production; we just need to ensure that appropriate incentives are put in place and appropriate decisions are made. We’ve got licenses in the market — cell-based vaccines, recombinant vaccines, high-dose vaccines, all of which — in the data we have — work better. What’s slowing down the shift away from egg-based vaccines is economics.” – by Caitlyn Stulpin


Atmar RL, et al. J Infect Dis. 2019;doi:10.1093/infdis/jiz545.

Flannery B, et al. J Infect Dis. 2019;doi:10.1093/infdis/jiz543.

Disclosures: Atmar, Flannery and Pavia report no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.