Virus World

New study spotlights influenza virus that could wreak havoc if it adapts to humans. What the world doesn’t need now is a pandemic on top of a pandemic. So a new finding that pigs in China are more and more frequently becoming infected with a strain of influenza that has the potential to jump to humans has infectious disease researchers worldwide taking serious notice. Robert Webster, an influenza investigator who recently retired from St. Jude Children’s Research Hospital, says it’s a “guessing game” as to whether this strain will mutate to readily transmit between humans, which it has not done yet. “We just do not know a pandemic is going to occur until the damn thing occurs,” Webster says, noting that China has the largest pig population in the world. “Will this one do it? God knows.”

When multiple strains of influenza viruses infect the same pig, they can easily swap genes, a process known as “reassortment.” The new study, published today in the Proceedings of the National Academy of Sciences, focuses on an influenza virus dubbed G4. The virus is a unique blend of three lineages: one similar to strains found in European and Asian birds, the H1N1 strain that caused the 2009 pandemic, and a North American H1N1 that has genes from avian, human, and pig influenza viruses. The G4 variant is especially concerning because its core is an avian influenza virus—to which humans have no immunity—with bits of mammalian strains mixed in. “From the data presented, it appears that this is a swine influenza virus that is poised to emerge in humans,” says Edward Holmes, an evolutionary biologist at the University of Sydney who studies pathogens. “Clearly this situation needs to be monitored very closely.” 

As part of a project to identify potential pandemic influenza strains, a team led by Liu Jinhua from the China Agricultural University (CAU) analyzed nearly 30,000 nasal swabs taken from pigs at slaughterhouses in 10 Chinese provinces, and another 1000 swabs from pigs with respiratory symptoms seen at their school’s veterinary teaching hospital. The swabs, collected between 2011 and 2018, yielded 179 swine influenza viruses, the vast majority of which were G4 or one of five other G strains from the Eurasian avianlike lineage. “G4 virus has shown a sharp increase since 2016, and is the predominant genotype in circulation in pigs detected across at least 10 provinces,” they write.

Original study published in PNAS (June 28, 2020):

https://doi.org/10.1073/pnas.1921186117

The influenza (flu) vaccine can not only prevent illness that may cause a week or more of misery, it can reduce the likelihood of hospitalization in children and death in adults, according to two analyses of Centers for Disease Control and Prevention (CDC)-supported U.S. influenza surveillance data being presented at IDWeek 2019.  The first study supports the benefit of flu vaccination in preventing severe outcomes in children. Children who received the influenza vaccine were half as likely to be hospitalized with flu as those who didn’t get vaccinated, according to the study, which followed more than 3,600 children over two seasons. The second study looked at more than 43,000 older adults hospitalized with flu over five seasons and found that vaccination reduced the risk of severe outcomes – including death, pneumonia, intensive care admission and mechanical ventilation – by more than one-third.

“These studies add to the evidence that influenza vaccines prevent serious complications from flu,” said Angela P. Campbell, MD, MPH, FIDSA, FPIDS, lead author of the study in children and medical officer in the Epidemiology and Prevention Branch of the Influenza Division at the CDC, Atlanta. “They show just how important it is that everyone six months and older who is eligible to get a flu vaccine does so every year.”

Flu vaccination in children reduces risk of hospitalization

In the first study, conducted by seven pediatric medical centers comprising the New Vaccine Surveillance Network, researchers analyzed flu test results from 3,630 children, aged 6 months to 17 years old, who were hospitalized with acute respiratory illness over two flu seasons in which influenza A(H3N2) viruses were the predominantly circulating virus. Patients were tested for influenza using molecular diagnostic tests: 163 out of 1,714 (10%) during the 2016-2017 season and 218 out of 1,916 (11%) during the 2017-2018 season tested positive for flu, including A(H3N2), A(H1N1) and B viruses. Researchers estimated how well the flu vaccine worked to reduce hospitalizations due to laboratory-confirmed influenza by comparing the frequency of flu vaccination among children who tested positive for flu to vaccination among children without flu, adjusting for age, race/ethnicity, enrollment month, study site and underlying medical conditions. Based on this information, the vaccine effectiveness against influenza-associated hospitalizations was 50% over the two seasons (49% for the first season and 51% the second), meaning that vaccination reduced the risk of hospitalization with flu by about half. “This is encouraging given that flu vaccines often work better against H1N1 and B flu viruses than against H3N2 viruses,” said Dr. Campbell. “Our findings support the use of vaccination to prevent severe flu illness in children during every flu season, regardless of which viruses are predominant.”

Flu vaccination in adults reduces risk of death

In the second study, researchers looked at five flu seasons using the U.S. Influenza Hospitalization Surveillance Network and identified 43,608 adults (18 and older) hospitalized with laboratory-confirmed flu. Overall, 38% of those 18 to 64 years old and 65% of those 65 or older had received a flu vaccine. Researchers assessed vaccination status among hospitalized patients to determine the reduction in the odds of severe outcomes among vaccinated patients compared to those who were unvaccinated. The findings showed that in patients diagnosed with influenza A(H1N1), flu vaccination reduced their odds of severe outcomes, including death, by 36%. Severe outcomes included death, pneumonia, admission to the intensive care unit and mechanical ventilation.

Flu vaccination in adults 18-64 with A/(H1N1) influenza was associated with reduced risk of the following: 36% death, 17% pneumonia, 19% intensive care unit (ICU) admission and 34% mechanical ventilation. Vaccination also was associated with a shorter ICU length of stay. Flu vaccination in those 65 years or older was associated with reduced risk of the following: 28% ICU admission, 46% mechanical ventilation. It was also associated with a shorter hospital length of stay.....

On January 31, 2019, an 11-year old boy in Japan went to a medical clinic with a fever. The providers there diagnosed him with influenza, a strain called H3N2, and sent him home with a new medication called baloxavir. For a few days, he felt better, but on February 5, despite taking the medication, his fever returned. Two days later, his 3-year-old sister also came down with a fever. She, too, was diagnosed with H3N2 influenza on February 8.

An analysis of flu samples collected from her and her brother show she was sickened by a strain of H3N2 harboring a new kind of mutation—one that Yoshihiro Kawaoka, University of Wisconsin-Madison professor of pathobiological sciences, says is resistant to baloxavir, is just as capable of making people sick as the non-mutated version, and is capable of passing from person to person. He and colleagues describe this in a study published today in Nature Microbiology that examined the effects of baloxavir treatment on influenza virus samples collected from patients before and after treatment. "We sequenced the entire viral genome of the 11-year-old boy with drug sensitive influenza virus (before treatment) and the sample from the girl that is drug resistant," says Kawaoka. "Out of 13,133 nucleotides, there was only one nucleotide difference between the two." 

In other words, what distinguished the virus collected from the brother before treatment and the virus collected from the sister later was a single mutation, a single change in just one letter among the more than 13,000 found in the genetic code of the virus. "It tells you the virus acquired resistance during treatment and transmitted from brother to sister," Kawaoka explains. Baloxavir is part of a new class of antiviral drugs that targets the machinery flu viruses use to copy their genetic material inside their human or animal hosts. It was first licensed in Japan, the United States, and in Hong Kong in 2018 and 2019. In fact, baloxavir represented 40 percent of the market share of influenza drugs in Japan during the 2018-2019 flu season. It will soon be licensed in 20 more countries, Kawaoka says. However, as he and his co-authors note in the paper, clinical trial data on the drug revealed that some patients infected with either H3N2 or H1N1 influenza who took baloxavir developed a mutation at position 38 of the polymerase acidic protein, part of the virus's machinery that is targeted by the drug. A previous study by another group showed that the particular mutation had not been described among 17,000 H3N2 virus samples catalogued prior to December 2018. "The new drug is safe, it went through phase three and was approved safety-wise, but even during clinical trials, the emergence of drug resistance was identified," Kawaoka explains. In fact, a previous study in pediatric patients showed the mutation appeared in the samples collected from nearly 1 in 4 of the 77 children enrolled who were also treated with baloxavir.

"Baloxavir-resistant viruses emerge with a relatively high rate in kids" says Kawaoka, also a professor of virology at the University of Tokyo.....For H1N1 influenza, the researchers tested 74 samples from patients before treatment (10 adults and 64 children), and 22 samples from patients both before and after treatment (7 adults and 15 children). There were no instances of mutation in any of the samples before treatment, but there were mutations in one adult and four children after, or in about 23 percent of patients. For H3N2, the team tested 141 patient samples before treatment (40 adults and 101 children), and two of those from children possessed the mutation. They also studied 16 patient samples before and after treatment (4 adults and 12 children), in which they found no mutations in adult samples but four of the child samples had the mutation.

Published in  Nature Microbiology (November 25, 2019):

https://doi.org/10.1038/s41564-019-0609-0

Toward the end of last year’s flu season — in about the middle of winter — flu experts noticed that the number of infections was not dropping, but picking up. A new virus seemed to be emerging, and it was making many Americans sick.  The virus was a type of H3N2 strain, and it started rapidly spreading among people in the United States before spreading into Europe, Canada, and South America. This put scientists worldwide who are tasked with determining what’s in the yearly flu vaccine on high alert. Did the flu vaccine for the 2019–2020 flu season need to be updated to protect against this new virus strain? The next flu season was still many months away, but it was time to scramble.

“Almost every year there is some kind of challenge,” says Dr. David Wentworth, a leading flu expert and chief of the U.S. Centers for Disease Control and Prevention’s (CDC) Virology, Surveillance, and Diagnosis Branch. “The thing about the flu is you have to be nimble.” One of the trickiest tasks for public health experts worldwide is creating the annual flu vaccine. The number of people who get sick from the flu each year depends largely on how well scientists predict what strains of the flu will be circulating and match them with a successful vaccine. “The flu virus evolves so fast,” says Wentworth. “It’s important to update the vaccine when it changes significantly enough to warrant it.”

The process of identifying the “right” viruses and producing enough flu vaccine for the nation starts with year-round study of flu viruses globally and ends with millions of Americans being vaccinated, the CDC says. While the effectiveness of each year’s flu vaccine can vary, the vaccine still prevents millions of illnesses, tens of thousands of hospitalizations, and thousands of deaths every year in the United States. And this year, the new vaccine does contain a new H3N2 strain. Flu experts worldwide, Wentworth says, are always prepared for the unpredictable. “We get kind of used to it with influenza because there are a lot of curveballs you need to respond to very rapidly,” he says. Wentworth and the CDC’s flu team led Elemental through their process for making this season’s flu vaccine.

How well the flu vaccine works in a given year depends partly on the match between the viruses used to make the vaccine and the viruses spreading among people during a given flu season. That’s why a year ago flu researchers started considering the newer H3N2 strain for this year’s vaccine. In fact, Wentworth and his team are already thinking about the vaccine for the 2020–2021 flu season.