‘We just have to keep pushing’: Universal flu vaccine remains out of reach, for now
Year after year, experts say the best defense against seasonal influenza is getting vaccinated.
However, overall seasonal influenza vaccine effectiveness has reached only 60% once in the past 10 years and is often less than 40%. As National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD, said earlier this year, “the world badly needs improved flu vaccines.”
“The Holy Grail, the universal flu vaccine, has to be one that protects against all strains of influenza — including those that have not yet emerged — and has long-lasting protection, meaning that it's not an annual vaccine, but one that could last many years,” Michael T. Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, said in an interview. “That's the goal. I think people will take even less than that.”
Former CDC Director Tom Frieden, MD, MPH, said an effective vaccine for tuberculosis or HIV would save more lives than an improved influenza vaccine, and a more effective vaccine against malaria “would save many more children’s lives.”
“But a more effective influenza vaccine would have major health and economic benefits and may be closer to reality than highly effective vaccines against other leading killers,” Frieden, now the President and CEO of Resolve to Save Lives, told Healio.
We spoke with Osterholm, Frieden and other experts about efforts to develop a universal influenza vaccine that can protect against pandemic and seasonal influenza and which technologies may hold the most promise.
“Vaccines are one of the greatest inventions of science, and it’s essential that we continue and increase our investment in a balanced portfolio: vaccine research and stronger systems to get vaccines to all people for whom they are indicated,” Frieden said.
Early studies show promise
According to an initiative spearheaded by WHO and CIDRAP, there are 114 novel influenza vaccine candidates under development by 105 developers, including 22 in clinical trials.
The initiative published the Influenza Vaccine Research & Development Roadmap in September.
“Our group has been very actively involved in flu vaccine research and development for some time,” Osterholm said. “We wrote a very important report that came out in 2012 which actually raised questions about how well the seasonal flu vaccines work. Traditional wisdom back then was that they work 70% to 90% of the time and we, of course, found that just wasn’t the case.”
Additionally, the 2009 H1N1 pandemic demonstrated that the vaccines developed for that virus “were far too late to have any major impact,” Osterholm said.
“While many promising universal influenza vaccine candidates are under study, clinical development requires overcoming a variety of significant technical and logistical challenges such as conducting clinical trials over multiple seasons with different circulating viruses,” the roadmap’s executive summary says.
The 114 vaccines in the roadmap’s tracker use six different vaccine platforms. According to Peter Palese, PhD, the Horace W. Goldsmith Professor and Chair of the department of microbiology at the Icahn School of Medicine at Mount Sinai in New York, the technologies have different targets.
“It is unlikely that one single technology will be the panacea,” he told Healio.
Osterholm and Palese said there have been many advances in just the last 5 years.
“We understand the structure of the virus and hemagglutinin” — the surface protein targeted by current vaccines — “in much greater detail, and we have a much greater insight into the immunology of the human host following infection by influenza viruses and following the administration of influenza virus vaccines,” Palese said.
At the NIH’s Vaccine Research Center, two nanoparticle influenza vaccine candidates have shown promise in early animal studies and advanced to human trials, according to NIAID allergist-immunologist Alicia T. Widge, MD. One of the vaccines removes the head of the hemagglutinin entirely — the part of the protein that mutates frequently and makes it necessary to update influenza vaccines.
“Your body basically just sees the stem,” Widge said. “Our goal is to make an immune response to the stem that’s more conserved between the different subtypes.” In essence, researchers are targeting a part of the hemagglutinin that is less likely to change from year to year.
Scientists at the NIAID developed the vaccine, called H1ssF_3928.
“It uses the iron storage protein ferritin,” Widge explained. “It basically self-assembles into these kind of nano particles that display the stem on its surface.”
The vaccine protected animals against several strains of influenza in challenge models, Widge said.
The human trial, which was launched in April 2019, enrolled 52 healthy adults aged 18 to 70 years who received the vaccine in one of two doses: either a single 20 µg intramuscular injection or two 60 µg injections spaced 16 weeks apart. Widge said they are still analyzing the results.
“We're really kind of hopeful that it's a big step toward creating a universal flu vaccine platform,” she said. “Now, it's sort of one step that by itself may not be a universal vaccine, but these are the steps we take to create one.”
A second NIH trial began earlier this year and is assessing a mosaic nanoparticle vaccine called FluMos-v1. According to NIH, the vaccine candidate was first tested in mice, ferrets and monkeys. Researchers compared the immune responses with those elicited by a commercially available influenza vaccine.
Widge said the results were so promising that the project has moved on to a phase 1 human trial, with the first healthy volunteer receiving the vaccine at the end of May. Widge and colleagues will assess the safety and immunogenicity of the vaccine among healthy adults aged 18 to 50 years.
They aim to enroll 35 participants — 15 will receive a licensed quadrivalent influenza vaccine and five will receive one 20 µg dose of the FluMos-v1. If there are no safety concerns, the remaining 15 volunteers will receive one 60 µg dose of the investigational vaccine.
“We kind of designed it in a different way,” Widge said. “This is a nanoparticle that displays all four of those hemagglutinins on its surface simultaneously. What we think this could do is sort of teach our immune system to respond to different subtypes of the flu and, again, hopefully create that stem-directed response that could protect against different strains.”
Widge said there are other labs all over the country studying universal influenza vaccine options.
“Some of them have kind of a similar approach, looking at directing the immune response toward the stem, but there are also a lot of creative approaches being taken all over,” she said.
Palese and a group of researchers at Mount Sinai, including microbiologists Florian Krammer, PhD, and Adolfo García-Sastre, PhD, developed a universal influenza vaccine candidate that also targets the hemagglutinin stalk, rather than its head.
“This is achieved by immunizing with chimeric hemagglutinin constructs” — mix-and-match head and stalks — “which induce long-lasting protective immune responses,” Palese explained.
They tested the safety and immunogenicity of these chimeric hemagglutinin-based vaccines in a phase 1 trial of healthy U.S. adults aged 18 to 39 years and published the results in Nature Medicine.
“We found that vaccination with adjuvanted, inactivated [chimeric hemagglutinin] vaccines induced remarkably high anti-stalk antibody titers, even after a single administration,” they wrote. “The titers achieved after one vaccination exceeded anti-stalk titer levels at which protection from pandemic H1N1 virus infection was observed in a Nicaraguan family cohort study.”
Palese and colleagues said the results suggest that “chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.”
According to Palese, phase 1/2 trials of the vaccines are underway.
‘Time will tell’
Widge said the COVID-19 pandemic has highlighted the need to increase pandemic preparedness for influenza.
“I think we’ll see high levels of activity in the flu field in the creation of better, more universal vaccines,” she said.
The pandemic also has contributed what experts agree could be an important technology for a universal influenza vaccine ⎼⎼ messenger RNA, which is used by two of the COVID-19 vaccines authorized for use in the U.S.
Frieden called mRNA vaccines “our pathway out of this pandemic.” In the shadow of the pandemic, Moderna and Sanofi Pasteur have both begun testing mRNA vaccines for influenza.
“Messenger RNA vaccines are an extremely promising technology that has been in the works for nearly 2 decades and can possibly be used to prevent and treat future infectious diseases and outbreaks — including, potentially, seasonal influenza,” Frieden said. “They also serve as a blueprint for vaccine production more broadly [by showing that the] creation of vaccine production hubs and transferring technology can create the capacity to rapidly produce millions of vaccine doses.”
Palese concurred, calling mRNA technology “revolutionary.”
“The mRNA technology is able to induce excellent immune responses against the protein, which is expressed from the mRNA,” he said. “Whether the mRNA technology is successful for universal influenza virus vaccines will depend on the constructs being used in the approach. If the latter is inducing protective immune responses, it should be successful. However, the jury is still out. Time will tell.”
Widge noted that mRNA vaccines can be manufactured quickly, are safe, and generate strong immune responses.
“One of the big advantages of mRNA vaccines, and one of the reasons we knew they would be exceptionally useful for pandemics, is you can really tailor the mRNA to express any proteins,” Widge said. “So, in the mRNA COVID-19 vaccines, they're expressing the spike protein, but you can very easily engineer mRNA to express a flu protein — whether that be the stem of the flu or other proteins as well.”
Osterholm said it is too early to say which technologies hold the most promise for universal influenza vaccine research, although he noted there are several outside of mRNA vaccines.
“The good news is that we have the opportunities at this point to really explore the landscape,” he said.
According to Frieden, investments to develop vaccines against two coronaviruses — SARS and Middle East respiratory syndrome — “dried up” after the outbreaks faded.
“Subsequent progress after those health threats were controlled was not as robust as it could have been if the interest in strengthening public health and more sustainable funding had been maintained,” he said. “This is our now-or-never moment in public health. We need to maintain the funding, momentum and interest in protecting ourselves against the next health threat, and not squander the gains we have made.”
Numerous institutions have received millions in federal funding for universal influenza vaccine projects, including Duke’s Human Vaccine Institute and Cincinnati Children’s Hospital. Duke’s three separate contracts with the National Institute of Allergy and Infectious Diseases could be worth $400 million alone if they are extended over the entirety of the 7-year project, the university reported in 2019, the same year President Donald J. Trump signed an executive order directing the federal government to “modernize” influenza vaccines.
Palese declined to predict when a universal influenza vaccine would be available to patients but indicated a lot of it has to do with funding.
“If we would spend as much money for flu as we have allocated for COVID-19, we would be there already, in my opinion,” he said.
Osterholm also could not say when a universal influenza vaccine might be available, but he hopes it will be sooner rather than later.
“We just have to keep pushing because we know that not only is the seasonal flu a challenge, we have to deal with the potential for pandemic influenza,” he said. “I think that’s a very important point to keep in mind.”
CDC. CDC seasonal flu vaccine effectiveness studies. https://www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm. Accessed Oct. 25, 2021.
Duke Vaccine Institute plays integral role in national effort to improve flu shots. https://corporate.dukehealth.org/news/duke-vaccine-institute-plays-integral-role-national-effort-improve-flu-shots. Published Sept. 30, 2019. Accessed Oct. 29, 2022.
NIH begins first-in-human trial of a universal influenza vaccine candidate. https://www.niaid.nih.gov/news-events/nih-begins-first-human-trial-universal-influenza-vaccine-candidate. Accessed on Oct. 15, 2021.
NIH launches clinical trial of universal influenza vaccine candidate. https://www.nih.gov/news-events/news-releases/nih-launches-clinical-trial-universal-influenza-vaccine-candidate. Accessed on Oct. 15, 2021.
University of Minnesota. The IVR Initiative. https://ivr.cidrap.umn.edu/ Accessed on Oct. 15, 2021.