By Gary Evans, Medical Writer
With the nation reeling from an historically bad influenza outbreak, the Centers for Disease Control and Prevention is preparing the public for a dismal efficacy estimate for the 2017-18 vaccine against the predominant H3N2 A flu strain.
“I think it’s important to say that we expect that the effectiveness against the H3N2 strains will be low,” said Anne Schuchat, MD, acting CDC director.
Flu seasons dominated by H3N2 can be particularly deadly, and comparison with past seasons suggests a heavy toll will be taken in the final counting for this season.
“The H3N2 years are the ones that have the higher number of deaths and that upper level is about 56,000 for the total year,” said Dan Jernigan, MD, director of the CDC’s influenza division.
While the CDC had initially projected a season-end efficacy in the 30% range, a recent interim report by Canadian researchers found the vaccine was only 17% effective against H3N2 influenza A.
“[That] is less than half that reported for the same A(H3N2) vaccine in 2016-17,” the researchers reported.1 “Our 2017-18 interim vaccine efficacy (VE) for influenza A(H3N2) is more comparable to the 2017 Southern Hemisphere interim VE of 10% reported from Australia.2 Mutations that arise from egg adaptation of the vaccine strain may affect VE, an issue also identified for the current season’s A(H3N2) vaccine component.”
Though most of this year’s vaccine is egg-based, the CDC wants to assess the efficacy of the cell-based vaccines currently in use.
“[With eggs] you can get very high yield, and that’s how we are able to get upwards of 151 million doses per year,” Jernigan said at a Feb. 2 CDC press conference. “There are some newer technologies that have been coming out. One is in the form of a recombinant vaccine with protein in the vaccine. The other one is grown in mammalian cells. Both the recombinant protein vaccine and the cell-grown vaccine don’t have to use eggs to grow. Therefore, it’s possible that those vaccine viruses may look more like what’s actually circulating out in the community.”
In addition, the agency wants to look at the egg-based vaccine’s effectiveness against the circulating strains of influenza B and H1N1 A that also are causing infections this year. The current vaccine should be more protective against those strains, which will figure into the CDC’s ultimate efficacy estimate of the season.
“It’s important with vaccine effectiveness estimates to know whether we’re talking about the total or against a particular strain,” Schuchat said. “We have been expecting low effectiveness against the H3N2 strains. So, I can’t say that I’m surprised about the Canada data. [We are] working hard to develop robust estimates for an interim look at effectiveness that we hope to release in the weeks ahead.”
The overall findings on vaccines and flu strains will inform the continued push for a “universal,” cell-based vaccine less vulnerable to antigenic drifts during production.
Death in the Otherwise Healthy
It is worth reiterating that vaccine efficacy is based on prevented infections, meaning immunization could still lessen the severity or prevent death. In that regard, the CDC reports that 80% of the 53 children who had died of flu as this report was filed were not vaccinated.
“We’re seeing serious influenza in children who really have no underlying conditions, including those who are very young,” Schuchat said. “[Some of the] warning signs are difficulty breathing, very high fever, rapid breathing — those are clues to call the doctor.” Children who seem to rebound only to rapidly decline again may have a bacterial coinfection that warrants immediate medical attention, she said.
In a CDC surveillance system that includes 2,800 physician offices and EDs, 7.1% of patients were reporting with flu-like illness. That represents a continuing increase from prior weeks as the current flu season approaches historic levels.
“We’ve had two seasons in the last 15 years that were higher than that,” Jernigan said. “The first was the 2009 H1N1 pandemic, which peaked at 7.8% and the [other was the] 2003-2004 season — a high severity H3N2 season — which peaked at 7.6%.”
By a different measure —hospitalizations — the current flu outbreak is approaching the 710,000 admitted with influenza in 2014-15. At the current pace, it was expected to surpass it. Another measure of how unusual by pandemic standards H1N1 was in 2009 was the number of hospitalizations.
“It wasn’t our peak for hospitalizations because as you remember we had a relative ‘sparing’ of the elderly, and the elderly account for quite a large proportion of hospitalizations,” Schuchat said.
The 2017-18 season has reverted to form with the most severe cases in those over 65, though there is a somewhat unusual trend of “baby boomers” over 50 comprising more cases than young people. The second most affected group this season has been age 50 to 64 years, with a rate of 44.2 per 100,000.
“The hospitalization rate for 50- to 64-year-olds this season is significantly higher than what was observed during recent seasons in 2012-13 and 2014-15,” Jernigan said. “When we look at actually what influenza viruses are sending [this age group] to the hospital this season, we see that not only is it H3N2, but also the other influenza A virus H1N1 that is contributing to these higher rates.”
The influenza A infections in those 65 and over are about 90% H3N2, but the figure is closer to 80% in the age 50 to 64 group.
“So, there’s about twice as much H1N1 proportionally causing disease in the 50- to 64-year-olds,” he said.
Can’t Breathe Easy
In a new study that provides little reassurance in the midst of an epic influenza season, researchers found that people with flu can shed the virus by simply breathing — suggesting that cough and other symptoms are not necessary for transmission.
In tests of 142 cases with symptomatic flu, the researchers found that infectious virus could be detected in 39% of fine-aerosol samples collected during 30 minutes of normal breathing. “[This] clearly establishes that a significant fraction of influenza cases routinely shed infectious virus, not merely detectable RNA, into aerosol particles small enough to remain suspended in air and present a risk for airborne transmission,” the report concluded.2
The study involved several institutions and was funded in part by the CDC. “Lack of human data on influenza virus aerosol shedding fuels debate over the importance of airborne transmission,” the researchers noted. “We provide overwhelming evidence that humans generate infectious aerosols.”
There are several intriguing findings in the data, but the study was not designed to determine, for example, whether patients with influenza should be on airborne precautions as opposed to contact and droplet isolation.
“We were sampling right up in the person’s face,” says lead researcher Donald K. Milton, MD, MPH, director of the Public Health Aerobiology, Virology, and Exhaled Biomarker Lab at the University of Maryland. “The CDC thinks that it is only up close that it matters. There is evidence from old experiments suggesting that flu can stay suspended in the air for a long time — for hours. I don’t understand why it wouldn’t be transmissible at a distance. It may be that as it gets away from the [source] person, it becomes more diluted.”
Regarding the isolation question, if subsequent research establishes flu as transmissible by exhaled aerosol over distance, it may be better to implement other engineering controls rather than adding another layer of PPE for healthcare workers, Milton says.
“I think the question really is, ‘How do we make healthcare facilities resistant to transmission of airborne infections?’” he tells Hospital Infection Control & Prevention. “If we found out — and we don’t know this yet — that influenza was transmissible at a distance via aerosols, that there was airborne transmission, then I think we would have to turn our attention away from airborne isolation rooms and PPE and start thinking of making the hospital a safer environment.”
The CDC usually recommends respiratory protection equivalent of an N95 respirator when a new virus emerges like the 2009 H1N1 pandemic flu, SARS in 2003, and MERS currently. This would not seem practical for seasonal influenza, so high vaccination levels and engineering controls like HEPA filtered air may be a more long-term solution.
“I trained in internal medicine, and in occupational health you talk about the hierarchy of controls,” Milton says. “The last thing you do is PPE. Engineering controls are much higher in the hierarchy.”
While the cases studied all had symptomatic flu, the presence of virus in exhaled breath also raises the issue of whether those with mild symptoms or in the initial stage of infection could transmit flu.
“[Researchers] published a paper3 a few years ago showing that in Great Britain, three-quarters of people who had flu didn’t have any symptoms at all,” Milton said. “Only about 20% of the people had symptoms in that category of feeling like you got ‘hit by a train.’ [They said] people with severe symptoms are the tip of the iceberg. We were seeing people with pretty solid symptoms. They didn’t all have fever, but they all had some significant symptoms and many of them had fever.”
The question of asymptomatic transmission goes beyond the scope of the study, but Milton has found evidence of this phenomenon in his work with ferrets, the preferred human surrogate in influenza research.
“There is data from the ferret model that suggests they shed virus in the air before they get sick,” he says. “Probably some people who do not have symptoms are shedding virus. How much? How infectious are they? We don’t know, but mathematical models suggest that they probably are.”
There has been considerable coverage of the study’s principal finding that influenza can be spread from exhaled breath in the absence of cough and sneezing. However, there was a subset of data in this same study that received less attention. If replicated in subsequent research, the finding could lead to a much more heretical conclusion: repeated immunization with egg-based, mismatched flu vaccine may undermine the protective immune response to subsequent flu infections. Eleven cases with a history of flu vaccination in the current and prior year during the study actually shed more virus than those with no history of prior vaccination.
“The association of current and prior year vaccination with increased shedding of influenza A might lead one to speculate that certain types of prior immunity promote lung inflammation, airway closure, and aerosol generation,” Milton and colleagues concluded. “This first observation of the phenomenon needs confirmation. If confirmed, this observation, together with recent literature suggesting reduced protection with annual vaccination, would have implications for influenza vaccination recommendations and policies.”
Indeed, that would certainly be a controversial finding if confirmed. Many healthcare workers are mandated to receive the annual flu vaccine, and the public anti-vaccine movement would no doubt seize on the finding as another reason to avoid immunization.
“It’s a robust finding even though it is only 11 people,” Milton says. “It’s one influenza season and the vaccine is different every year, so you can’t generalize very far from it. But there are animal models that suggest that when you have a mismatched vaccine and then antibodies that do not neutralize the virus, the antibodies can have the effect of blocking your cellular immune response from being as effective. My takeaway from it is that it is time to ditch the egg-based vaccine.”
Again, the current mismatch with H3N2 influenza A has been ascribed to a mutation of the vaccine virus while it is being prepared in eggs.
“The egg-based vaccine is repeatedly showing this problem of not being very effective, and this [finding in the 11 patients] is probably a corollary of that,” Milton says. “When the vaccine is slightly off, the virus has mutated within the eggs. It has to adapt back to a bird virus in order to grow in eggs. The [vaccine strain] is not what we are being infected with, and that’s the problem.”
The H3N2 flu strain, which first emerged 50 years ago in 1968, seems particularly prone to mutation during vaccine production, Jernigan said. “This is something that we have been following for several years,” he said. “It’s something that has developed incrementally over time. It is a problem with H3N2. When you take these viruses and try and get them to grow in eggs, they make changes that make it very difficult for them to stay similar to what is actually out there circulating.”
As a result, H3N2 eludes human immunity and causes severe infections and a high mortality rate.
“We know that H3 causes worse disease,” Jernigan said. “Exactly why, still needs to be figured out. It’s amazing how much it’s still able to evade the human immune system.”
- Skowronski DM, Chambers C, De Serres G, et al. Early season co-circulation of influenza A(H3N2) and B(Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018. Eurosurveillance 2018; 23(5). Available at: http://bit.ly/2Ex4fge.
- Paules CI, Sullivan SG, Subbarao K, et al. Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine. New Engl J Med 2018; 378:7-9.
- Yan J, Grantham M, Pantelic J, et al. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. Proc Nat Acad Sci USA Dec. 15, 2017: Early Edition:doi:10.1073/pnas.1716561115.
- Hayward AC, Fragaszy EB, Bermingham A, et al. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Resp Med 2014;2(6):445–454.