Are we closer to vaccines that will protect us against influenza’s many diverse strains? An interview with pioneering scientist Peter Palese.

It’s February, and it doesn’t look like the perennial flu bug is leaving anytime soon. The US Centers for Disease Control and Prevention’s most recent weekly update, ending Jan. 27, reports that this season is breaking all kinds of records. The percentage of outpatient visits for flu-like symptoms was 7.7%, the highest it’s been all year. The number of deaths attributed to pneumonia and influenza are also unusually high, according to the CDC.

To make matters worse, this year’s flu shot has proven less effective than usual. This is due in part to unexpected changes in the H3N2 strain, which is the most common flu subtype circulating in the Northern and Southern Hemispheres. Most flu vaccines are grown in chicken eggs, but while this year’s batch was being incubated, the virus mutated in the eggs and became less effective for vaccines.

Getting a flu shot, even a modestly effective one, is still better than going without. Yet scientists have long acknowledged the need for alternatives to the traditional way that we design influenza vaccines. The hemagglutinin (HA) molecule that juts out from the surface of the influenza virus continually mutates, requiring vaccine developers to update the seasonal influenza vaccines every year in order to adapt the vaccine to the two to three dominant strains they predict will be in circulation that year. Finding better approaches has been a global public health priority, and there are now real signs of progress.

One of them is the push for universal vaccines that are designed to protect more people against a broader range of influenza viruses for a longer period of time. Once a long-shot idea, there are now several universal vaccine trials in humans, including vaccine candidates developed by Peter Palese, Florian Krammer and Adolfo Garcia-Sastre in the department of microbiology at the Icahn School of Medicine at Mount Sinai in New York.

Palese is one of the pioneers in this field. Eight years ago, his lab made a seminal discovery when it used mice to demonstrate the production of a handful of rare, broadly neutralizing monoclonal antibodies against an array of H3N2 viruses. These are the same viruses that are responsible for most of the influenza morbidity in the last 43 years. The Mount Sinai researchers determined that these rare antibodies worked by inhibiting viral fusion, and identified the binding site of one of the monoclonal antibodies on the stalk of the HA as a continuous region that was 100% conserved between the H3 viruses used in the study. 

Based on these findings the Mount Sinai researchers developed novel vaccine constructs which were sufficiently immunogenic to induce antibodies against multiple subtypes. Palese and his colleagues from Mount Sinai now have a universal influenza vaccine candidate in Phase 1 safety studies.

Other research groups are also racing to develop universal vaccine candidates. The most advanced is Oxford University’s candidate, which made headlines last month by being the first universal influenza vaccine candidate to be tested beyond phase I clinical trials. The two-year study will enroll 2,000 people.

The US National Institute of Allergy and Infectious Diseases (NIAID) is also developing influenza vaccine candidates that either elicit antibodies that target the stem of the HA protein, or incorporate four subtypes of the HA protein into one vaccine. NIAID is using non-infectious virus-like particles to construct the vaccine.

Eureka Editor Regina McEnery caught up with Dr. Palese last week to learn how his research is progressing and whether we should give up on the seasonal flu shot. Here are his edited responses.

The universal influenza vaccine candidate that Mount. Sinai developed is finally in human clinical trials. How does the vaccine candidate work?

PP: We have designed vaccine constructs that can target the conserved stalk or stem of the hemagglutinin protein. If you think of the HA protein as a mushroom, by silencing the head we can redirect our immune system to the conserved regions on the stalk. Our vaccine consists of a live-attenuated universal influenza virus prime and an inactivated universal influenza boost.

Why is targeting a conserved region important in making an effective universal flu vaccine?

PP: The vaccine constructs, which in essence consist of the conserved domains of the virus, will induce protective immune responses against all influenza viruses carrying these conserved (non-changing) domains.

Can you provide some details about the trials?

PP: They are both Phase 1 safety trials. GSK (GlaxoSmithKline) is sponsoring one of them. It began in September and will enroll several hundred people. A second trial, which began in October, is being funded by the Gates Foundation. That one will enroll about 65 people.

What preclinical evidence is there that universal flu vaccination might work?

PP: There are publications showing universal flu vaccines are protective in mice and ferrets, but the proof of the pudding is whether the candidates will induce protective immune responses in humans, and whether the responses will be long-lasting. Using surrogate markers, we should know within a year whether this is something that is going to work, or whether it is not good enough to replace what we have.

What surrogates will you be using to measure efficacy of the universal influenza vaccine?

PP: We will test whether sera from vaccinated humans will have broadly protective antibodies against many different influenza virus variants.

Influenza vaccine research is really hot now. What recent technological advances are helping propel influenza research forward, particularly for universal vaccination?

PP: We can make influenza viruses in the lab using reverse genetics. Mount. Sinai researchers in collaboration with Dr. Terry Tumpey from the CDC used this approach to reconstruct the 1918 virus, the so-called Spanish flu that infected about a third of the world’s population, killing an estimated 100 million people. This technology is something we need in order to make universal vaccines that can work. Also, structural analysis is showing us how antibodies capable of neutralizing many viruses are binding to influenza viruses and where these conserved regions of the virus that they binding to are.

Before we sign off, what is your opinion of the yearly flu shot?

PP: We have influenza vaccines which are better than their reputation, but a lot of people just don’t do it even though the CDC says every American should be vaccinated. My argument is that if I’m vaccinated and I get the flu it is much, much milder than if I’m not vaccinated.

 

Learn more about Charles River’s vaccine development services and catch our upcoming post about why the usual hype surrounding flu season is justified this year.