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Experts Warn of Severe Influenza, Low Vaccine Efficacy

Janis C. Kelly
December 04, 2017

Infectious disease experts from the US National Institutes of Health and the World Health Organization (WHO) warn that current approaches to seasonal influenza vaccine development have left the United States relatively defenseless against the influenza A (H3N2) strain now making its way over from the Southern hemisphere.

Writing in a recent perspectives article in the New England Journal of Medicine, the authors, including Catharine I. Paules, MD, and Anthony S. Fauci, MD, from the Office of the Director, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, and Sheena G. Sullivan, MPH, PhD, and Kanta Subbarao, MB, MPH, from the WHO Collaborating Center for Reference and Research on Influenza, Melbourne, Australia, say data from the recent influenza season in Australia should put the United States on alert regarding the upcoming influenza season.

Moreover, they call for a "transformative approach" to a universal vaccine, rather than the seasonal, strain-specific one currently used. They also recommend ditching egg-based vaccine propagation in favor of cell culture or the recombinant DNA baculovirus system.

Dr Paules and colleagues note that confirmed influenza cases in Australia reached 215,280 by mid-October, which is dramatically higher than the 59,000 cases reported during the 2009 pandemic.

And if that were not sufficiently unwelcome news, the authors further note that preliminary data put the H3N2 vaccine efficacy at about 10%. This is the same vaccine currently being used in the United States.

One factor in this dismal efficacy is thought to be a mismatch between strain-specific vaccines recommended by the WHO and the circulating influenza strains. However, "[e]ven in years when influenza vaccines are well matched to circulating viruses, estimates of vaccine effectiveness range from 40 to 60%, which is lower than that for most licensed non-influenza vaccines," Dr Paules and colleagues write.

A second factor for low efficacy is that most influenza-vaccine viruses are propagated in eggs, and the vaccine virus changes during egg-based production in ways that facilitate replication in eggs but reduce vaccine effectiveness against circulating virus.

A key change appears to be a mutation in the hemagglutinin (HA) protein that mediates receptor binding by neutralizing antibodies, according to a recent study from researchers at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. The researchers identified an HA glucosylation site that was lost during egg adaptation but remained in circulating influenza A (H3N2) strains.

That difference between the vaccine and circulating strains might have contributed to low vaccine efficacy during the 2016-2017 season in the United States. Corroborating that view, the team found that most participants who had a strong antibody response to the circulating strains had received a vaccine produced in a recombinant DNA baculovirus system, which does not trigger viral changes.

Preliminary data suggest that egg adaptation changes in HA may also have contributed to the poor vaccine efficacy in the recent Australian influenza season, according to Dr Paules and colleagues.

Because most of the US influenza-vaccine supply is produced in eggs and the 2017-2018 Northern Hemisphere vaccine is identical to that used in Australia, the result may be low vaccine effectiveness against influenza A (H3N2) viruses and a relatively severe influenza season in the United States.

"This possibility underscores the need to strive toward a 'universal' influenza vaccine that will protect against seasonal influenza drift variants as well as potential pandemic strains, with better durability than current annual vaccines," the authors conclude. "Among other advantages, in all likelihood, such a vaccine would not be subject to the limitations of egg-based vaccine technology."

"What encourages me about this piece is the acknowledgment that the 1930s influenza vaccine technology is not really up to the task," Heath A. Kelly, MD, adjunct professor of infectious disease epidemiology at the National Centre for Epidemiology and Population Health, Australian National University in Canberra, told Medscape Medical News.

"When I first started researching influenza vaccine effectiveness, it was evident that killed sub-unit vaccines did not seem to reflect the marketing hype. This was at a time when both the CDC [Centers for Disease Control and Prevention] and the WHO were claiming that influenza vaccines were 70% effective, a claim that was difficult to sustain... It is understandable that public health authorities would not want to undermine confidence in vaccines in general and influenza vaccines in particular, but it is an open question whether overstating influenza vaccine effectiveness is good for public confidence. That is why it is refreshing to see an honest statement of the problem."

Dr Kelly added, "There is absolutely no doubt we need a different approach to vaccine development and manufacture, but if the technology were easy, we would have it sorted by now."

The authors and Dr Kelly have disclosed no relevant financial relationships.

SOURCE: December 04, 2017. N Engl J Med. Published online November 29, 2017.





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