Influenza, cancer and HIV: After the success of Covid, what next for mRNA vaccines? | medical research

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It’s one of the pandemic’s most remarkable success stories: the unproven technology that delivered Moderna and Pfizer/BioNTech vaccines in record time, helping turn the tide on Covid-19. Vaccines rely on mRNA, the molecule that directs our cells to make certain proteins. By injecting synthetic mRNA, our cells turn into bespoke vaccine factories, pumping out any protein we want our immune system to learn to recognize and destroy.

In the pre-pandemic era, technology was viewed with suspicion – a smart concept, but not guaranteed to deliver. Now there is growing confidence that mRNA vaccines can have far-reaching applications in treating diseases from influenza to malaria.

flu

Every February, influenza scientists participate in an annual ritual: Bets are placed at a WHO meeting that will be dominated by flu strains the following winter. There are four influenza viruses in circulation, each of which evolves so rapidly that the previous year’s vaccines lose their effectiveness. Manufacturers need at least six months to produce the vaccines, a laborious process that involves growing an attenuated virus inside millions of chicken eggs. When influenza forecasts are on target, vaccines can be 60% effective, but mismatches between vaccines and circulating strains can result in efficacy as low as 10%.

The Holy Grail of influenza research is a universal vaccine that will work across all four strains and continue to work for future incarnations as their genomes change over time. Such a vaccine would need to target an essential influenza protein that does not change much from strain to strain. But our immune systems do not respond strongly to this part of the virus, so the goal has remained elusive for decades. However, mRNA production is so fast and easy that vaccines can be designed to hit many loci simultaneously. “It is likely that such a vaccine would be able to induce protective responses on a large scale,” said Norbert Bardi, a microbiologist at the University of Pennsylvania. His team is working on a candidate vaccine that uses about 12 pieces of messenger RNA and is designed to work across many strains of influenza. The team hopes to begin human trials in 2023.

cancer

The HPV vaccine, which protects against the virus that causes most cervical cancers, already prevents thousands of cases of cancer each year. In the future, scientists hope that mRNA vaccines can be used to inoculate against cancer itself by teaching the immune system to recognize mutations before they occur, in an entirely new therapeutic approach. “We are taking advantage of the known genetic advances of cancer,” said Professor Herbert Kim Laerley, who works on cancer vaccine technology at Duke University.

His team plans to trial an mRNA vaccine next year in patients with late-stage breast cancer, where tumors typically develop unresponsive to drugs by acquiring mutations in certain genes. Again, the advantage of mRNA is the ability to hit multiple targets simultaneously – in this case, a handful of potential mutations. “There is no better surgeon in the world than your own immune system to get rid of these [mutated cells] Lyrley said.

If the first applications are successful, they could extend a patient’s life for months by keeping the cancer out for even longer. Ultimately, it may be possible to prevent cancer in some high-risk groups such as heavy smokers, where a mutation in a gene called KRAS causes up to a quarter of cancers.

malaria

In October, the World Health Organization approved the release of the first malaria vaccine. But there is room for improvement, as the RTS,S vaccine reduces severe malaria by 30%. The primary challenge is that the malaria parasite has developed a way to block immune memory. Even after contracting malaria, let alone getting vaccinated, people remain susceptible to infection again, and the disease kills 500,000 people a year, mostly infants and children.

In 2012, Professor Richard Bokala, of Yale University School of Medicine, and colleagues discovered that malaria caused “immune system memory loss” using a protein called PMIF, which kills memory T cells. Bukkala is working on a form of an RNA vaccine that will immunize against PMIF.

Studies in mice suggest that blocking the protein allows the immune system to clear malaria faster, leading to milder disease and, most importantly, future immunity. Bokala has teamed up with scientists at Oxford’s Jenner Vaccine Institute to test the candidate, and if the results are positive, they hope to begin human trials next year.

“Vaccines are urgently needed in the developing world for parasitic diseases that have long hampered the economic and societal development of many countries,” Bukala said. “Not only has RNA enabled the PMIF vaccine to be successful, but the platform is much less expensive than protein-based vaccines, opening up opportunities for a malaria vaccine that didn’t exist before.”

human immunodeficiency virus

“We are now in the fifth decade of a global HIV epidemic,” said Derek Kane, of the Duke University Human Vaccine Institute. So far, a vaccine has remained elusive.

Caine’s team focused on a subset of HIV patients (less than a third) who eventually develop specialized antibodies that can neutralize HIV years after infection. By this time there is a huge reservoir of virus in the body, and it is too late to clear the infection. “It is as if you have found a fire extinguisher, but the whole house is already on fire,” Cain said. However, if a vaccine can stimulate these antibodies, the hope is that they can eliminate HIV before it takes hold.

Cain and his colleagues have meticulously mapped the immune system’s twisting path to create these highly specialized antibodies, and as part of a consortium, they are creating a series of four or five multi-target mRNA vaccines designed to “re-establish the arms race between the immune system and pathogens.”

“We certainly think that an HIV vaccine would be far from the most complex vaccine we’ve had to use in the population,” Cain said. “We don’t expect it to work 100% or 90% like the Covid vaccines, but even if we could get to 50-60% it would work; 70% would be amazing.”

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