By Gary Evans, Medical Writer

The National Institutes of Health is ramping up research to develop a universal flu vaccine, both to prepare for the next pandemic and prevent the kind of mismatch that may occur this season with an H3N2 strain that caused severe infections in Australia, a top infectious disease expert says.

Anthony Fauci, MD, director of the NIH National Institute for Allergy and Infectious Diseases (NIAID), told Hospital Infection Control & Prevention that the U.S. may be in for a “rough” influenza season due to a vaccine mismatch with the circulating H3N2 virus.

A recent paper from Fauci and colleagues cites problems with the traditional use of chicken eggs to make the seasonal flu vaccine. These include the vaccine’s vulnerability to seasonal flu mutations, which appears to be the case this year with the H3N2 influenza A virus.

With the preceding flu season in the Southern Hemisphere often predictive of what the U.S. will face, it does not bode well that Australia reports “record-high numbers of laboratory-confirmed influenza notifications and outbreaks, and higher-than-average numbers of hospitalizations and deaths,” Fauci and colleagues reported.¹

“The number of notifications reached 215,280 by mid-October, far exceeding the 59,022 cases reported during the 2009 H1N1 influenza pandemic, according to the Australian Government Department of Health,” they warned. “H3N2 viruses predominated, and the preliminary estimate of vaccine effectiveness against influenza A (H3N2) was only 10%.”

Given the high mutability of influenza virus, things always are subject to change and the vaccine efficacy in the U.S. will not be clear until well into or after the current flu season, Fauci says.

“But having said that, generally we kind of have the same season in our winter that the Southern Hemisphere had in their winter, which was six months ahead of us,” he says. “So, since we are using the same vaccine that was used in Australia and it looks like the virus now is similar to the virus that was circulating in Australia, it is likely — not definite, but likely — that we will have a rough season with influenza. Whether [the vaccine] is going to be 10% effective — or 15%, 20%, or 5% — it is very difficult to put an exact number on it. But the one thing that we do know is that the vaccine that was grown in eggs is a bit of a mismatch with the circulating virus.”

That said, flu immunization still is strongly recommended to protect against other circulating strains and gain as much immunity as possible to the H3N2 strain. As infection preventionists are well aware, the old adage holds that even a partially effective flu shot can keep you out of the hospital or the morgue.

Scrambled Eggs

It appears the meager 10% efficacy against H3N2 in the current vaccine was caused by a viral mutation as the targeted strain was being grown in chicken eggs. According to the report by Fauci and colleagues, the “egg-propagated vaccine viruses acquired changes in the HA [hemagglutinin] that subsequently altered antigenicity against circulating strains,” they concluded. “This observation lends credibility to the hypothesis that egg-adapted changes contribute to poor influenza vaccine effectiveness.”

In essence, the H3N2 vaccine strain mutated while it was being incubated, antigenically drifting away from the necessary match with the wild strain of the virus. “It mutated at a very critical point in the virus — the point that was needed for vaccine [efficacy],” Fauci says. “So even though you put a matched virus into the eggs, what ultimately came out of the eggs was an accidental mismatch due to the mutation.”

There is a cell-based vaccine available that was created without using chicken eggs, and thus would presumably be less susceptible to the vagaries of the 70-year-old egg production method.

The CDC does not recommend the cell vaccine over the egg-based vaccine, saying, “while the use of cell-grown reference viruses and cell-based technology may offer the potential for better protection over traditional, egg-based flu vaccines because they result in vaccine viruses that are more similar to flu viruses in circulation, there are no data yet to support this. There is no preferential recommendation for one injectable flu vaccine over another.”²

While cell-based vaccine is promising technology, the bulk of flu vaccine supply will be produced using eggs for the time being.

As a result of these type of problems and the threat of the next flu pandemic, the NIH recently held a workshop with flu experts to develop new platforms for vaccine production.³ The idea is to replace egg production with a new platform — a recombinant DNA technology-based platform that could be used to make a universal vaccine effective against multiple flu strains.

Thus, workshop participants outlined an initial goal of a universal influenza vaccine with 75% efficacy that would provide prolonged protection against influenza A strains, which caused pandemics in 1918, 1957, 1968, and 2009. While researchers hope to eventually achieve a vaccine efficacy greater than 90%, the initial goal of 75% would be beyond the 60% or less immunity conferred in annual flu vaccinations.

Under current methods, it may take up to six months to create a vaccine for an emerging pandemic virus. While the 2009 outbreak was not considered severe by pandemic standards, the fear is that a flu strain eventually will emerge that is both highly virulent and easily transmissible. The 1918 H1N1 influenza pandemic killed at least 50 million people globally and possibly twice that. The virus had a striking virulence and emerged before antibiotics were available to treat bacterial co-infections. It is probably most remembered in epidemiological annals for causing an inflammatory immune response, the infamous “cytokine storm” that killed so many young and healthy people. H5N1, aka “bird flu,” has caused mortality in the 60% range when it gets into humans, but it has not yet developed the means to transmit effectively from person to person.

Duration of Immunity

The duration of immunity conferred by a universal flu vaccine is one of the unresolved issues at present, but the ultimate goal is to add flu shots to the childhood immunization schedule, Fauci explains.

“There are going to be several iterations of universal flu vaccine,” he says. “It is going to be like universal vaccine 1.0, 2.0, 3.0. First, you want to get a vaccine that covers multiple strains. Then we want one that not only covers multiple strains, but has immunity that lasts for several years. The end game isn’t for one year — that’s a start. We would like to have a universal flu vaccine that you could give to children when they get the measles vaccine. Like a couple shots — one when you are one year old and another when you’re four to six years old.”

To do this, NIH researchers and their partners are trying to develop a vaccine that would confer immunity to all HA subtypes, which could be protective against influenza A without necessarily having to create a new vaccine each year.

“For example, we regularly get H3N2 and H1N1 viruses,” Fauci says. Those are the two major ones that for the last couple of decades have been prevalent. Yet we have to change the vaccine almost every year. The reason is there are slight shifts in this subtype. A universal flu vaccine will cover those changes.”

Such a vaccine also would be a major public health bulwark against pandemic flu, possibly eliminating the need to rapidly produce a vaccine once it becomes clear that an antigenic shift has occurred in the virus and there will be little existing human immunity.

Though the 2009 virus was not as lethal as some of its pandemic predecessors, it showed how a much more virulent strain of flu could spread rapidly across the globe.

“It was a pandemic by definition because it was a brand-new virus that most of the population — except the very elderly — had never experienced,” Fauci says.

“It was widespread and occurred throughout the world, so by definition it was a pandemic. However, in terms of severity it was relatively mild. In terms of epidemiology it was a pandemic, but from a pathogenicity standpoint it was not severe.” A more virulent flu virus in the next pandemic “is entirely possible, which is why we are putting such an effort into developing a universal flu vaccine,” Fauci says.

The 2009 H1N1 influenza pandemic also exposed the vulnerabilities of the current vaccine production system, as the virus rapidly emerged before the vaccine could be produced.

At the opening plenary of IDWeek 2017 in San Diego, Fauci showed a slide of grim-faced public health officials — including himself — being grilled by Congress after the 2009 pandemic flu emerged before the vaccine was ready. They had projected the vaccine would be available for the winter flu season of 2009-2010, but it struck early via children returning to school that fall. Another surprise about that pandemic is that it emerged in Mexico and California, confounding traditional expectations that flu arises and disseminates out of East Asia.

“We were really fooled,” Fauci said at the conference. “The outbreak occurred before the vaccine became available. What this lesson told us is that we certainly need a universal influenza vaccine — without a doubt — to take off the table the drifts and the shifts, and the lack of preparedness.”

REFERENCES

1. Paules CI, Sullivan SG, Subbarao K, et al. Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine. New Engl J Med November 29, 2017 DOI: 10.1056/NEJMp1714916.
2. CDC. Frequently Asked Flu Questions 2017-2018 Influenza Season. Available at: http://bit.ly/2rkXwPk. Accessed Dec. 5, 2017.
3. Paules CI, Marston HD, Eisinger RW, et al. The Pathway to a Universal Influenza Vaccine. Immunity 2017;47(4):599-603.