SCIENTISTS ARE WORKING ON "EVERYTHING VACCINES" / THE ECONOMIST

Immunology

Scientists are working on “everything vaccines”

A single jab could protect against a wide range of pathogens

A circle of syringes pointing inwards / Illustration: Timo Lenzen

THE VITAL importance of vaccines is most apparent when they fall short. 

The covid-19 pandemic showed how quickly a new virus can spread while scientists race to catch up with jabs. 

Fast-evolving viruses can also evade existing protections. 

Each year’s flu vaccine is designed based on scientists’ best guess about which strains will dominate, given what was circulating the season before. 

In 2025 the H3N2 strain developed several mutations after the World Health Organisation had selected which variants should be included, blunting the vaccine’s effectiveness. 

The result was an early and severe flu season in both America and Europe.

These shortfalls are an inevitable consequence of how vaccines work. 

They train the immune system to recognise specific features on the outer surfaces of pathogens. 

But these features can change. 

One response is to speed up the production of jabs to match new variants. 

There is another strategy, though. 

What if vaccines could be made to protect against a family of viruses, like influenza or coronaviruses, rather than just individual members of them? 

More tantalising still—what if a single jab could protect against many families of viruses, bacteria and even allergens?

Most vaccines work by priming the part of the immune system that responds to infection from its memory of past encounters. 

This “adaptive” system consists mainly of B and T cells armed with receptors that recognise specific antigens—molecules on the surfaces of viruses or bacteria. 

When a new pathogen appears in the body, the immune cells with matching receptors find the foreign invader and start replicating themselves. 

This process can take several days, which allows infections to spread meanwhile. 

After that first exposure, though, some of these immune cells persist in the body as memory cells.

Vaccines exploit this by presenting a harmless version of an antigen in advance. 

In coronavirus vaccines this is part of the spike protein; in influenza it is usually the head of the haemagglutinin protein, which gives flu viruses their “H” classification (for example H1N1). 

Both of these proteins allow the viruses to enter host cells. 

These are, however, also the parts of the virus most prone to mutation, allowing pathogens to evade the memory cells.

One way to make vaccines more effective across different versions of a virus is to design them to target the features that change less often. 

Pamela Bjorkman of the California Institute of Technology (Caltech) and her colleagues have developed a “mosaic” coronavirus vaccination that is made up of tiny molecular footballs, with 60 surfaces. 

Each surface is studded with a fragment of spike protein. 

In one version of the vaccine eight different spike-protein subsections are arranged randomly over the surfaces, one from SARS-CoV-2 (the covid-19 virus) and the rest from different sarbecoviruses, a group of SARS-like viruses found in animals.

When tested on mice and macaques, the vaccine created an immune response to parts of the spike protein that are common across all the viruses in the sample. 

The immune system’s B cells have two arms that each hold a receptor, and they bind most strongly when both arms can latch onto the same target. 

Faced with the mosaic, the B cells that target the conserved (ie least-changing) parts of the spike proteins bound most successfully. 

These B cells were then scaled up inside the body and saved as memory cells. 

The researchers found that their vaccine protected animals against the original SARS virus, which was not included in the mosaic.

Such complex molecules are difficult to manufacture and regulate for use in humans, though. 

To get around this, the researchers are developing a messenger RNA (mRNA) version of the jab that, when injected, instructs an animal’s own cells to assemble the vaccine. 

The strings of mRNA encode multiple variants of the spike protein, as well as instructions on how to create a mosaic ball using the cell’s own membrane. 

This involves a molecule that transports the spike-protein fragments to the cell surface and another which recruits machinery from inside the cell to make the section of membrane bud off into bubble-like vesicles. 

In effect this creates the tiny mosaic vaccine balls from the cell’s own surface.

Other scientists are applying similar ideas to influenza. 

Researchers at Duke University have created 80,000 variations of the influenza surface protein haemagglutinin and injected this mixture into mice and ferrets. 

Their vaccine provided broad protection against different flu strains by forcing the immune system to develop responses to the conserved stalk region of the protein, rather than the variable head part. 

“That’s the checkmate,” says Nicholas Heaton, who led the study. 

“The virus can’t get around it.”

Some human trials of broad-spectrum vaccines are already underway. 

But the work is becoming entangled in politics. 

America’s health secretary, Robert F. Kennedy junior, has called for research on vaccines targeting what he describes as “natural immunity”, while expressing scepticism about mRNA. 

Many of the most promising broad-spectrum approaches right now, however, depend on mRNA. 

One trial, funded under Mr Kennedy’s new regime, is testing a flu vaccine made from mixtures of whole inactivated viruses. Some researchers are sceptical that will generate such a broad response to different strains.

All these broad-spectrum approaches rely on the same principles as conventional jabs: training the adaptive immune system to recognise specific features of a pathogen, albeit ones that are less likely to change. 

But in a new study at Stanford University, researchers took a different approach. 

Rather than training the immune system to memorise particular pathogens, they wanted to put the lungs into a constant state of readiness, allowing fast responses to almost any invading germ.

This approach relies partly on the innate immune system, a faster but less specific set of defences made up of cells including macrophages, which can engulf pathogens and destroy them. 

For decades it was assumed that the innate immune system lacked any memory, but more recent research has suggested otherwise.

The insight came from an unlikely source: the century-old Bacillus Calmette-Guérin (BCG) tuberculosis vaccine. 

Scientists have long known that after the rollout of the BCG jab the mortality rate from other types of infections also fell dramatically. 

This led researchers to discover that the innate immune system can in fact be trained. 

The BCG jab, for example, tweaks the degree to which certain genes in immune-system cells are switched on or off. 

These changes cause the cells to stay on high alert. 

They also cause T cells to travel to the lungs, where they use signalling molecules, known as cytokines, to continue activating the innate immune system.

The Stanford team set out to recreate this effect. 

They created a vaccine in a nasal spray that combined two components. 

The first was a molecule that triggered the cells of the innate immune system to immediately spring into action. 

The second was a harmless egg protein that acted as an antigen. 

This caused T cells to travel to the lungs, where they continued to activate the innate immune cells for months.

The team put a drop of the vaccine into the noses of mice four times over several weeks. 

They found that mice vaccinated in this way were protected against SARS-CoV-2 and related coronaviruses, with viral levels in their lungs around 700 times lower than in unvaccinated animals. 

The effects lasted for at least three months. 

Next the team tried bacteria, and found the mice also fended off infection from Staphylococcus aureus and Acinetobacter baumannii. 

Even their response to allergens was reduced. 

“It’s a beautiful paper,” said Mihai Netea, a professor of immunology at Radboud University in the Netherlands, who was not involved in the study.

Though exciting, it is still early days. 

The Stanford researchers hope to test their vaccine in humans next and are currently fundraising for a phase 1 trial. 

They think their vaccine fits Mr Kennedy’s desire for broad-spectrum vaccines based on “natural immunity”. 

But even if politics allows, biology may not. 

Results in mice often fail to translate into humans. 

There is also a huge degree of genetic diversity in immune responses across people.

Most scientists see these types of broad-spectrum vaccines as complementary to traditional antigen-specific vaccinations. 

“Traditional vaccines have been tried and tested for two centuries,” said Bali Pulendran, who led the Stanford study. 

Universal jabs may not last as long or protect as strongly against specific variants. 

But in the inevitable event of a new virus spilling over into humans, or a mutated flu strain emerging just as winter begins, the world would be thankful for them.