The predominant circulating influenza virus this season is a poor match with the vaccine, meaning that antiviral drug treatments may be critical for the protection of high-risk patients.

The CDC issued a public health notice that influenza A (H3N2) is the predominant circulating virus.1 Researchers and public health officials have previously reported that the vaccine strain of H3N2 is a poor match, with some efficacy estimates as low as 10%.2

The CDC expects vaccine efficacy to be similar to last season’s 32% for H3N2, but that still leaves many people vulnerable.

“In the past, A(H3N2) virus-predominant influenza seasons have been associated with more hospitalizations and deaths in persons aged 65 years and older and young children compared to other age groups,” the CDC reported. “For this reason, in addition to influenza vaccination for prevention of influenza, the use of antiviral medications for treatment of influenza becomes even more important than usual. The neuraminidase inhibitor (NAI) antiviral medications are most effective in treating influenza and reducing complications when treatment is started early. Evidence from previous influenza seasons suggests that NAI antivirals are underutilized in outpatients and hospitalized patients with influenza who are recommended for treatment.”

The CDC recommended that all hospitalized patients and high-risk outpatients with suspected influenza should be treated as soon as possible with an NAI antiviral.

“While antiviral drugs work best when treatment is started within two days of illness onset, clinical benefit has been observed even when treatment is initiated later,” the CDC noted. “The CDC recommends antiviral medications for treatment of influenza as an important adjunct to annual influenza vaccination. Treatment with neuraminidase inhibitors has been shown to have clinical and public health benefit in reducing illness and severe outcomes of influenza.”

In addition to recommending antiviral treatment for hospitalized patients with flu, the CDC said the following risk groups should be administered antivirals if they exhibit influenza-like illness:

• a patient who has severe, complicated, or progressive illness. This may include outpatients with severe or prolonged progressive symptoms, or who develop complications such as pneumonia but who are not hospitalized;

• children younger than two years and adults aged 65 years and older;

• people with chronic pulmonary problems, including asthma; cardiovascular, renal, hepatic, hematological, and metabolic disorders, or neurologic and neurodevelopment conditions such as stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury;

• people with immunosuppression, including that caused by medications or by HIV infection;

• women who are pregnant or postpartum (within two weeks after delivery);

• people aged younger than 19 years who are receiving long-term aspirin therapy;

• American Indians/Alaska Natives;

• people with extreme obesity (i.e., body mass index is equal to or greater than 40);

• residents of nursing homes and other chronic care facilities.

A Shot for All Seasons

Against this backdrop, the National Institutes of Health (NIH) is accelerating development of a universal flu vaccine, both to prepare for the next pandemic and prevent the kind of mismatch that has occurred this season. (For more information, see the story in the January 2018 issue of HEH.)

The NIH recently held a workshop with flu experts to develop new platforms for vaccine production.3 The idea is to replace the traditional flu vaccine method of incubating the virus in eggs with something like a recombinant DNA technology-based platform that could be used to make a universal vaccine effective against multiple flu strains.’

NIH researchers are trying to develop a vaccine that would confer immunity to all hemagglutinin (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,” says Anthony Fauci, MD, director of the NIH National Institute for Allergy and Infectious Diseases. “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.”

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 endgame 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.”

NIH 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 achieve a vaccine efficacy greater than 90% eventually, 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 will eventually 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.

A universal 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,” he says.

The unintended consequences of developing seasonal flu vaccine in chicken eggs were underscored by the current mismatch with H3N2 A virus.

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. “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.”4

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

REFERENCES

1. CDC Health Alert Network. Seasonal Influenza A(H3N2) Activity and Antiviral Treatment of Patients with Influenza. Dec. 27, 2017. Available at: http://bit.ly/2E9AstE. Accessed Dec. 29, 2017.

2. Paules CI, Sullivan SG, Subbarao K, et al. Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine. New Engl J Med Nov. 29, 2017. DOI: 10.1056/NEJMp1714916.

3. Paules CI, Marston HD, Eisinger RW, et al. The Pathway to a Universal Influenza Vaccine. Immunity 2017;47(4):599-603.

4. CDC. Frequently Asked Flu Questions 2017-2018 Influenza Season. Available at: http://bit.ly/2rkXwPk. Accessed Dec. 29, 2017.