Perspective

CDC prepares new H7N9 vaccine as human cases spike

The CDC has begun preparing a new avian influenza A(H7N9) vaccine amid a spike in cases in China and evidence that the deadly virus has split into two strains, including one that does not seem to be susceptible to existing vaccines.

A record 460 human cases of H7N9 have been reported since Oct. 1 in China — more than 36% of the overall number of 1,258 cases that have been seen in the region since the virus emerged in 2013.

According to CDC analysis published in Morbidity and Mortality Weekly, H7N9 has split into two distinct lineages. One strain, named for the Yangtze River Delta, has undergone antigenic changes as it circulates among poultry in China and is now showing reduced susceptibility to existing vaccines. Of 74 virus samples from patients or live bird markets in China that were tested by the CDC since October, 93% were from this Yangtze River Delta strain. The other strain, named for the Pearl River Delta, is still susceptible to existing vaccines.

Antigenic changes in H7N9 make it likely that existing vaccines will have a reduced effectiveness against the virus, so experts from WHO’s Global Influenza Surveillance and Response System this week recommended two new compositions based on the new strain.

“Frankly, the bigger picture is that all avian influenza A viruses continue to evolve,” Timothy M. Uyeki, MD, medical epidemiologist in the CDC’s Influenza Division and one of the authors on the new report, told Infectious Disease News. “For pandemic planning purposes, we need to keep up with these antigenic changes and develop candidate vaccine viruses to match them.”

Old vaccines based on 2013 viruses

Until now, H7N9 vaccines — including those stored in the U.S. — have been based on viruses taken after H7N9’s emergence in 2013. The two new candidate vaccines recommended by the WHO experts are based on viruses from the Yangtze River Delta lineage: a highly pathogenic A/Guangdong/17SF003/2016-like virus, and a low pathogenic A/Hunan/2650/2016-like virus. The CDC is preparing a vaccine based on the low pathogenic H7N9 strain — the form of the virus that has accounted for all but a handful of the human infections since 2013, Uyeki said.

According to the HHS Office of the Assistant Secretary for Preparedness and Reponses, the U.S. will need 20 million doses of the vaccine to ensure that health care professionals and emergency responders would be protected against the virus if it starts to spread widely from person to person.

H7N9 has a case fatality rate of 41%. Historically a low pathogenic virus, it is starting to show changes, with analysis of samples in China showing that it has evolved to a highly pathogenic form for the first time in poultry. Three human cases — a small percentage — have also shown characteristics of this change.

“Now the question is: What are the implications for a change in this virus from a low pathogenic to a highly pathogenic form? We don’t know what that will mean in infected humans, but one possibility is that we might see even more severe disease and [a] higher mortality [rate],” Uyeki said. “But I want to emphasize that, without this change, the mortality [rate] already has been quite high in infected humans. It actually has more implications for the agricultural sector, for the poultry industry.”

More difficult to treat

There also is troubling evidence that treating viruses in the newest H7N9 epidemic has become more difficult. Uyeki and colleagues said 7% to 9% of the viruses that have been analyzed since October have known or suspected markers of reduced susceptibility to neuraminidase inhibitors, the class of antivirals commonly prescribed to treat influenza viruses, including H7N9.

No people or poultry in the U.S. have ever been infected with H7N9, but travelers to China could be at risk, especially if they visit live poultry markets.

“If the viruses circulating in poultry develop resistance to these neuraminidase inhibitors, then treating a patient with a resistant virus would likely not be effective, and that would be very frightening to public health,” Uyeki said. “If you take neuraminidase inhibitors out of the equation for treatment, it basically comes down to supportive care.”

Although the CDC said the clinical characteristics and risk factors for humans appear unchanged for H7N9, concerns apparently remain over the virus’ potential to cause a pandemic, which can occur when novel animal influenza viruses mutate and begin infecting humans, who have little or no immunity to the new pathogens. Unlike seasonal epidemics, which happen mostly in winter and are covered by the seasonal influenza vaccine, pandemics can last for a year or more and often leave public health agencies scrambling to respond.

The most recent influenza epidemic occurred in 2009 when a new influenza A(H1N1) “swine flu” replaced the old epidemic “Spanish flu” strain — the one that killed approximately 50 million people during the 1918 pandemic. As many as 18,300 people died in the U.S. during the 2009 pandemic.

Of the 460 human cases that have been identified so far in the fifth H7N9 epidemic in China since 2013, 453 were from mainland China, six were associated with travel to mainland China from Hong Kong, Macao or Taiwan and one was an asymptomatic case in a poultry worker in Macao.

Although limited human-to-human spread of H7N9 continues to be identified in China, Uyeki and colleagues said there has been no evidence of sustained transmission. They categorized the risk to the public as “low,” but noted that H7N9 has the highest risk score among 12 novel influenza A viruses that have been assessed by a tool developed in 2013 by the CDC and outside experts to appraise their potential to cause pandemics.

Uyeki said nosocomial transmission of H7N9 has been reported in China in different hospitals and is a real concern for clinicians. He added that patients who have suspected or confirmed H7N9 infection should be isolated in an airborne infection isolation room.

“It’s not just droplet precautions, it’s airborne precautions,” Uyeki said. “We want to make sure that the number of caregivers is limited, that they’re educated and trained, and they’re equipped with the recommended personal protective equipment. We want to prevent nosocomial transmission, both of a sensitive virus and a resistant virus in the health care setting.”

Clinicians can find complete guidance for evaluating patents with possible H7N9 infection at this link. – by Gerard Gallagher

Disclosure: The researchers report no relevant financial disclosures.

The CDC has begun preparing a new avian influenza A(H7N9) vaccine amid a spike in cases in China and evidence that the deadly virus has split into two strains, including one that does not seem to be susceptible to existing vaccines.

A record 460 human cases of H7N9 have been reported since Oct. 1 in China — more than 36% of the overall number of 1,258 cases that have been seen in the region since the virus emerged in 2013.

According to CDC analysis published in Morbidity and Mortality Weekly, H7N9 has split into two distinct lineages. One strain, named for the Yangtze River Delta, has undergone antigenic changes as it circulates among poultry in China and is now showing reduced susceptibility to existing vaccines. Of 74 virus samples from patients or live bird markets in China that were tested by the CDC since October, 93% were from this Yangtze River Delta strain. The other strain, named for the Pearl River Delta, is still susceptible to existing vaccines.

Antigenic changes in H7N9 make it likely that existing vaccines will have a reduced effectiveness against the virus, so experts from WHO’s Global Influenza Surveillance and Response System this week recommended two new compositions based on the new strain.

“Frankly, the bigger picture is that all avian influenza A viruses continue to evolve,” Timothy M. Uyeki, MD, medical epidemiologist in the CDC’s Influenza Division and one of the authors on the new report, told Infectious Disease News. “For pandemic planning purposes, we need to keep up with these antigenic changes and develop candidate vaccine viruses to match them.”

Old vaccines based on 2013 viruses

Until now, H7N9 vaccines — including those stored in the U.S. — have been based on viruses taken after H7N9’s emergence in 2013. The two new candidate vaccines recommended by the WHO experts are based on viruses from the Yangtze River Delta lineage: a highly pathogenic A/Guangdong/17SF003/2016-like virus, and a low pathogenic A/Hunan/2650/2016-like virus. The CDC is preparing a vaccine based on the low pathogenic H7N9 strain — the form of the virus that has accounted for all but a handful of the human infections since 2013, Uyeki said.

According to the HHS Office of the Assistant Secretary for Preparedness and Reponses, the U.S. will need 20 million doses of the vaccine to ensure that health care professionals and emergency responders would be protected against the virus if it starts to spread widely from person to person.

H7N9 has a case fatality rate of 41%. Historically a low pathogenic virus, it is starting to show changes, with analysis of samples in China showing that it has evolved to a highly pathogenic form for the first time in poultry. Three human cases — a small percentage — have also shown characteristics of this change.

“Now the question is: What are the implications for a change in this virus from a low pathogenic to a highly pathogenic form? We don’t know what that will mean in infected humans, but one possibility is that we might see even more severe disease and [a] higher mortality [rate],” Uyeki said. “But I want to emphasize that, without this change, the mortality [rate] already has been quite high in infected humans. It actually has more implications for the agricultural sector, for the poultry industry.”

More difficult to treat

There also is troubling evidence that treating viruses in the newest H7N9 epidemic has become more difficult. Uyeki and colleagues said 7% to 9% of the viruses that have been analyzed since October have known or suspected markers of reduced susceptibility to neuraminidase inhibitors, the class of antivirals commonly prescribed to treat influenza viruses, including H7N9.

No people or poultry in the U.S. have ever been infected with H7N9, but travelers to China could be at risk, especially if they visit live poultry markets.

“If the viruses circulating in poultry develop resistance to these neuraminidase inhibitors, then treating a patient with a resistant virus would likely not be effective, and that would be very frightening to public health,” Uyeki said. “If you take neuraminidase inhibitors out of the equation for treatment, it basically comes down to supportive care.”

Although the CDC said the clinical characteristics and risk factors for humans appear unchanged for H7N9, concerns apparently remain over the virus’ potential to cause a pandemic, which can occur when novel animal influenza viruses mutate and begin infecting humans, who have little or no immunity to the new pathogens. Unlike seasonal epidemics, which happen mostly in winter and are covered by the seasonal influenza vaccine, pandemics can last for a year or more and often leave public health agencies scrambling to respond.

The most recent influenza epidemic occurred in 2009 when a new influenza A(H1N1) “swine flu” replaced the old epidemic “Spanish flu” strain — the one that killed approximately 50 million people during the 1918 pandemic. As many as 18,300 people died in the U.S. during the 2009 pandemic.

Of the 460 human cases that have been identified so far in the fifth H7N9 epidemic in China since 2013, 453 were from mainland China, six were associated with travel to mainland China from Hong Kong, Macao or Taiwan and one was an asymptomatic case in a poultry worker in Macao.

Although limited human-to-human spread of H7N9 continues to be identified in China, Uyeki and colleagues said there has been no evidence of sustained transmission. They categorized the risk to the public as “low,” but noted that H7N9 has the highest risk score among 12 novel influenza A viruses that have been assessed by a tool developed in 2013 by the CDC and outside experts to appraise their potential to cause pandemics.

Uyeki said nosocomial transmission of H7N9 has been reported in China in different hospitals and is a real concern for clinicians. He added that patients who have suspected or confirmed H7N9 infection should be isolated in an airborne infection isolation room.

“It’s not just droplet precautions, it’s airborne precautions,” Uyeki said. “We want to make sure that the number of caregivers is limited, that they’re educated and trained, and they’re equipped with the recommended personal protective equipment. We want to prevent nosocomial transmission, both of a sensitive virus and a resistant virus in the health care setting.”

Clinicians can find complete guidance for evaluating patents with possible H7N9 infection at this link. – by Gerard Gallagher

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Florian Krammer

    Florian Krammer

    The ongoing fifth wave of human infections with avian H7N9 viruses in China has so far resulted in an unprecedented number of cases. Although the clinical characteristics of the disease and risk factors for acquiring the infection did not change, the surge in the number of cases is alarming. It is unlikely that a fully avian influenza virus like H7N9 will cause a new pandemic. However, H7N9 infections usually occur during the winter months and overlap with seasonal influenza virus epidemics. Coinfections of humans with seasonal H1N1 or H3N2 viruses and H7N9 might lead to the emergence of novel reassortant viruses that have the genetic make-up to cause a pandemic. The risk for this to happen increases with the number of H7N9 infections, which makes this fifth H7N9 wave especially problematic.

    In addition, virus isolates from this latest H7N9 wave have diverged into two lineages, and existing vaccines seem to cover only one of the lineages. Furthermore, viruses with potentially increased resistance to neuraminidase inhibitors as well as viruses that incorporated a multi-basic cleavage site into their hemagglutinin have been detected. The latter is a hallmark of high pathogenicity in poultry, similar to that observed with avian H5N1 viruses. These developments are worrisome and require close monitoring of the situation in China. Now more than ever we need to push the development of novel therapeutics and broadly protective influenza virus vaccines to enhance our pandemic preparedness.

    • Florian Krammer, PhD
    • Associate professor in the department of microbiology Icahn School of Medicine at Mount Sinai, New York

    Disclosures: Krammer reports that his laboratory receives funding from the National Institute of Allergy and Infectious Diseases, GlaxoSmithKline, PATH, and the Bill and Melinda Gates Foundation, and that the Icahn School of Medicine at Mount Sinai has filed several patent applications regarding influenza virus vaccines.