Influenza research update

Aug. 22, 2018
Editor’s note: ‘Tis the season—the flu season, that is, and labs will soon be busy with all the diagnostic testing that requires. In the meantime, here’s a roundup of some recent research news.

Obesity extends duration of flu A virus shedding

Obesity, which increases influenza disease severity, also extends by about 1.5 days how long influenza A virus is shed from infected adults compared to non-obese adults, according to a multi-year study of two cohorts of Nicaraguan households. The findings implicate chronic inflammation caused by obesity as well as increasing age as reasons for extended viral shedding, which puts others at risk of infection.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), provided primary study funding through its Centers of Excellence for Influenza Research and Surveillance (CEIRS) program. University of Michigan researchers coordinated the study in collaboration with colleagues at the Nicaraguan Ministry of Health, the Sustainable Sciences Institute in Nicaragua, and the University of California-Berkeley.

The researchers monitored 1,783 people from 320 households in Managua, Nicaragua, during the three flu seasons between 2015 and 2017. Overall, 87 people became ill with influenza A and 58 with influenza B. As defined by body mass, obesity was found in two percent of the people up to age four, nine percent of those ages five to 17, and 42 percent of those ages 18 to 92. Obese adults with two or more symptoms of influenza A (n=62) shed the virus 42 percent longer than non-obese adults—5.2 days, compared to 3.7 days. Obese adults with one or no symptoms of influenza A (n=25) shed the virus 104 percent longer than non-obese adults—3.2 days compared to 1.6 days. Obesity was not a risk factor for increased viral shedding duration in children ages five to 17 or for adults with influenza B.

According to the researchers, the amount and duration of viral shedding likely affects how efficiently influenza viruses are transmitted to others. Obesity alters the immune system and leads to chronic inflammation, which also is known to increase with age. The authors propose that chronic inflammation caused by obesity may be responsible for increased influenza A viral shedding. The researchers are continuing to study the correlations among obesity, inflammation, and viruses. However, they note that reducing obesity rates could be an important target to limit the spread of viral infectious diseases. The study also notes that obesity rates range widely throughout the world: in 2014, adult obesity in the United States was 35.5 percent, compared to 17.4 percent in Nicaragua and 4.4 percent in other low-income countries.

Clues for improved influenza vaccine design

Influenza vaccines that better target the influenza surface protein called neuraminidase (NA) could offer broad protection against various influenza virus strains and lessen the severity of illness, according to new research published in the journal Cell. Current seasonal influenza vaccines mainly target a different, more abundant influenza surface protein called hemagglutinin (HA). However, because influenza vaccines offer varying and sometimes limited protection, scientists are exploring ways to improve vaccine effectiveness. The new research builds on previous studies of NA and was conducted by a team of scientists including investigators from the CEIRS program.

Investigators analyzed blood samples from people who were vaccinated against influenza and people diagnosed with either the 2009 H1N1 influenza virus or H3N2 influenza viruses. The volunteers were recruited for this study or had taken part in prior influenza research studies. The analyses indicate that influenza vaccines rarely induce NA-reactive antibodies, whereas natural influenza infection induces these types of antibodies at least as often as it induces HA-reactive antibodies. Additional studies in mice reinforced the human data, indicating that current influenza vaccines do not induce NA-reactive antibodies efficiently.

Additional laboratory experiments show that the NA-reactive antibodies induced during natural influenza infection are broadly reactive, meaning they could potentially protect against diverse strains of influenza. To test this theory, scientists isolated NA-reactive monoclonal antibodies from the H3N2 and H1N1 influenza patients (N2-reactive antibodies and N1-reactive antibodies, respectively). They administered 13 N2-reactive antibodies to mice and subsequently infected the mice with a different H3N2 virus strain. Eleven of the 13 N2-reactive antibodies partly or fully protected the mice. They also administered eight N1-reactive antibodies to mice and subsequently infected the mice with a similar H1N1 virus strain or an H5N1-like virus strain. Four of the eight antibodies completely protected the mice against both virus strains.

The authors note that the findings suggest that influenza vaccines should be optimized to better target NA for broad protection against diverse influenza strains. In this regard, NIAID is supporting research to characterize NA responses in infected and vaccinated individuals and to determine the mechanism of action of NA protection. NIAID also supports “NAction!” a CEIRS working group that identifies knowledge gaps in our understanding of NA and sets NA research priorities for improved influenza vaccines. These efforts contribute to NIAID’s larger plan to develop a universal influenza vaccine—a vaccine that can durably protect all age groups against multiple influenza virus strains.

Annual vaccination doesn’t prevent natural immunity

Earlier studies have suggested that having repeated annual influenza vaccination can prevent natural immunity to the virus, and potentially increase the susceptibility to influenza illness in the event of a pandemic, or when the vaccine does not “match” the virus circulating in the community.

But now, researchers at the Influenza Centre in Bergen (Norway) have published an important study which concludes that annual influenza vaccination does not increase susceptibility to influenza infection in years of vaccine mismatch.

These findings are important because they show that having annual influenza vaccination is only a positive thing, and they support continuing the policy of repeated annual vaccination, says Professor Rebecca Cox, Head of the Influenza Centre.

Over a period of five years, researchers at the Centre followed 250 healthcare workers. They were vaccinated in 2009, and either had annual vaccination in all subsequent seasons or no further vaccination between 2010 and 2013. Three thousand blood samples were collected. The results showed that both healthcare workers who had annual vaccination and those who were not annually vaccinated had the same second-line defense, but those who had gotten annual vaccines had a better first-line defense. The group that had annual vaccination were not prevented from developing natural immunity.

Almost 1.5 million people in Norway have an increased risk of influenza complications. The influenza vaccine is annually updated to adapt to the rapid virus evolution. It is the only vaccine that is recommended on an annual basis.

For people in the risk groups, influenza could lead to pneumonia and exacerbation of chronic underlying diseases. Influenza can result in hospitalization, and in the elderly this may lead to institutionalization and, in the most severe cases, death. “That is why it is so important that we can continue to recommend annual vaccination, especially now that we know that it does not prevent natural immunity,” says Cox.

How flu shot manufacturing forces virus to mutate

According to a new study from scientists at The Scripps Research Institute (TSRI), the common practice of growing influenza vaccine components in chicken eggs disrupts the major antibody target site on the virus surface, rendering the flu vaccine less effective in humans.

“Now we can explain—at an atomic level—why egg-based vaccine production is causing problems,” said TSRI Research Associate Nicholas Wu, PhD, first author of the study, published recently in the journal PLOS Pathogens.

For more than 70 years, manufacturers have made the flu vaccine by injecting influenza into chicken eggs, allowing the virus to replicate inside the eggs, and then purifying the fluid from the eggs to get enough of the virus to use in vaccines.

The subtype of influenza in this study, H3N2, is one of several subtypes shown to mutate when grown in chicken eggs, and the researchers say the new findings add support to the case for alternative approaches to growing the virus.

“Any influenza viruses produced in eggs have to adapt to growing in that environment and hence generate mutations to grow better,” explains study senior author Ian Wilson, D.Phil.

The new study shows exactly why egg-based manufacturing is a problem for the H3N2 subtype. As H3N2 influenza has become more prevalent, scientists formulating the seasonal flu vaccine have sought to include this virus and teach the human immune system to fight it. Despite this effort, recent flu vaccines have proven only 33 percent effective against H3N2 viruses.

Wu used a high-resolution imaging technique called X-ray crystallography to show that—when grown in eggs—the H3N2 subtype mutates a key protein to better attach to receptors in bird cells. Specifically, there was a mutation called L194P on the virus’s hemagglutinin glycoprotein (HA). This mutation disrupts the region on the protein that is commonly recognized by our immune system.

This means a vaccine containing the mutated version of the protein will not be able to trigger an effective immune response. That leaves the body without protection against circulating strains of H3N2.

In fact, Wu’s analysis shows that the current strain of H3N2 used in vaccines already contains this specific mutation L194P on HA. “Vaccine producers need to look at this mutation,” cautions Wu.

The researchers say that further studies are needed to investigate replacing the egg-based system. “Other methods are now being used and explored for production of vaccines in mammalian cells using cell-based methods and recombinant HA protein vaccines,” says Wilson.“There’s a huge need for flu vaccine research,” adds Wu.

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Courtesy of NIAID, NIH
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