Scientists are trying a new approach to developing vaccines that could lead to the production of a flu vaccine capable of effectively targeting a wide range of flu viruses. This could then be helpful in curtailing hospitalizations and reducing healthcare costs.

The radical approach that UCLA scientists are developing involve identifying and eliminating the defense mechanisms of a virus at the genome level. In their study, which was published in the journal Science, scientists altered influenza virus to stimulate strong immune responses in animals.

UCLA scientists first focused on identifying the parts of the influenza virus genome responsible for its anti-interferon properties — a process that took four years to realize. After determining the functions of every amino acid in the influenza virus genome, scientists deactivated the sequences that hamper the stimulation of interferons in the immune system. This way, they could ensure that interferon production would be greater when the vaccine is used.

Interferons are proteins released by cells in response to entry of viruses into body. They are the first line of defense against invading viruses, and they also coordinate the adaptive immune responses that lead to long-term protection against viruses. The latter principle is actually the one that is vital to vaccination, or the administration of antigenic material to produce a lasting protection against a disease.

The problem, however, is the fact that viruses are smart microorganisms. They have managed to develop their own ways to evade detection of the immune system, thereby limiting the stimulation of much-needed interferons to deal with them. For this very reason, UCLA scientists found the need for developing a new approach to creating vaccines.

“If viruses do not induce interferons, they will not be killed in the first-line defense; and without interferons, the adaptive immune response is limited,” the study’s senior author Ren Sun, who is a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and of bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science, said. “For these reasons, viruses have evolved strategies to evade detection and limit the production of interferons by host organisms.”

It’s worth mentioning that researchers have been disabling genetic sequences that prevent interferon induction for some time now. Unlike before however, UCLA scientists are disabling multiple interferon-evasion sites on the virus. “Other researchers have knocked out one anti-interferon sequence, but we knocked out eight locations by changing one amino acid at a time,” the study’s first author Yushen Du, who recently earned her doctorate at UCLA, said.

According to the study, the engineered influenza virus that no longer has interferon-evasion functions generates very strong immune responses. The virus is of course weakened in typical hosts to ensure that it is safe as it is effective. “With this approach, the safety and efficacy requirement of vaccines can potentially be achieved simultaneously. In traditional vaccine development, one is usually sacrificed for the other,” Sun explained.

The new approach has helped UCLA scientists develop a vaccine candidate that could be used against flu viruses. “Because the variations of seasonal influenza viruses can be unpredictable, current vaccines may not provide effective protection against them. Previous pandemics and recent outbreaks of avian influenza highlight the need to develop vaccines that offer broader, more effective protection,” Sun said.

The vaccine candidate still needs thorough evaluation and it also needs the approval of the FDA before it can be circulated commercially. For now, Sun and his colleagues are focused on testing the vaccine in animals with two strains of influenza. After this, they could move to doing clinical trials with humans. Sun is also encouraging other scientists to try the new approach in creating other vaccines for a wide range of viruses.

The flu vaccine could get a much-needed boost

New approach developed at UCLA could help curtail hospitalizations due to influenza infection

Chase Doyle | January 18, 2018

National Institute on Allergy and Infectious Diseases, NIH

Influenza virus particles. UCLA scientists developed a new technique to identify and eliminate the virus’s defense mechanisms.

More than 700,000 Americans were hospitalized due to illnesses associated with the seasonal flu during the 2014–15 flu season, according to federal estimates. A radical new approach to vaccine development at UCLA may help lower that figure for future flu seasons.

The scientists used leading-edge genomics to identify and eliminate the virus’s defense mechanisms, enabling them to develop a vaccine “candidate” — meaning that it must still undergo evaluation and approval by the FDA — that in animals has been proven to be safe and highly effective against influenza.

In the study, which was published in the journal Science, the engineered influenza virus induced strong immune responses in animals. While further research will be needed, the UCLA scientists are hopeful that their approach could lead to a new, more effective vaccine that can be taken as a nasal spray at home, rather than as an injection by a health professional.

UCLA 孙仁教授团队研制出新的“超干扰素敏感”（HIS）流感毒株

“Because the variations of seasonal influenza viruses can be unpredictable, current vaccines may not provide effective protection against them," said Ren Sun, a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and the study’s senior author. “Previous pandemics and recent outbreaks of avian influenza highlight the need to develop vaccines that offer broader, more effective protection.”

The key to the new vaccine is an understanding of the interactions between the virus and interferons, which are proteins that are critical to the body’s immune response. Interferons have two main functions：one is a first line of defense to kill invading viruses very quickly; a second is to coordinate the adaptive immune responses, which provide long-lasting protection against the virus. The latter is the basis of vaccination.

“If viruses do not induce interferons, they will not be killed in the first-line defense; and without interferons, the adaptive immune response is limited,” said Sun, who also is a professor of bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science. “For these reasons, viruses have evolved strategies to evade detection and limit the production of interferons by host organisms.”

Sun and colleagues have spent the past four years searching the influenza virus’s entire genome for its anti-interferon properties. After defining the function of every amino acid in the genome, they deactivated the sequences that prevent interferon induction, which meant that interferon production would be highly stimulated in organisms infected with the virus.

“By disabling these interferon-evasion functions, the engineered virus is weakened in typical hosts,” said Yushen Du, the study’s first author, who recently earned her doctorate at UCLA. “At the same time, however, due to interferon stimulation, the engineered virus generates very strong immune responses.”

Sun added：“With this approach, the safety and efficacy requirement of vaccines can potentially be achieved simultaneously. In traditional vaccine development, one is usually sacrificed for the other.”

Although researchers have disabled genetic sequences that block interferon before, the UCLA scientists were the first to systematically identify and eliminate multiple interferon-evasion sites at single amino acid resolution on the virus.

“Other researchers have knocked out one anti-interferon sequence, but we knocked out eight locations by changing one amino acid at a time,” Du said.

Sun and his colleagues now plan to test the vaccine in animals with two strains of influenza before moving to clinical trials with humans. He said the approach could also be applied to developing vaccines against a wide range of other viruses.