The biotechnology that delivered the Pfizer/BioNTech and Moderna vaccines in record time is one of the most successful stories during the pandemic. mRNA-based vaccines rely on a molecule that instructs our cells to produce specific proteins. By injecting synthetic mRNA, our cells transform into on-demand vaccine factories, pumping out any protein we want our immune system to be trained to recognize and destroy. Prior to the pandemic, this technology was viewed with skepticism. However, there is now increasing confidence that mRNA vaccines could have far-reaching applications for treating diseases, from influenza to malaria.
### Addressing Influenza Mutations
Scientists studying influenza participate every February in an annual ritual, laying bets at a World Health Organization meeting dominated by the strains of influenza expected in the upcoming winter. There are currently four circulating influenza viruses, each evolving so quickly that last year's vaccines lose their effectiveness. Manufacturers need at least six months to produce vaccines, a complicated process that involves growing weakened virus in millions of chicken eggs! When flu predictions are accurate, vaccines can be up to 60% effective, but mismatches between vaccines and circulating strains can reduce efficacy to as low as 10%. The solution is a universal vaccine that would work across all four strains and continue to function as their genomes change over time. Such a vaccine would need to target the core influenza protein, which does not change much from strain to strain. However, our immune systems do not respond strongly to this part of the virus, making it an elusive target for decades.
Fortunately, producing mRNA is very fast and easy, allowing for vaccine designs that target multiple goals simultaneously. Norbert Pardi, a microbiologist at the University of Pennsylvania, told The Guardian: "Such a vaccine is likely to evoke broadly protective responses." His team is working on a candidate vaccine that uses about 12 pieces of mRNA designed to work across multiple influenza strains. They hope to begin human trials in 2023.
### Vaccination Against Cancer
The human papillomavirus (HPV) vaccine, which protects against the virus responsible for most cervical cancers, currently prevents thousands of cancer cases each year. In the future, scientists hope to use mRNA vaccines to immunize against cancer itself by teaching the immune system to recognize mutations before they occur, representing an entirely new therapeutic approach. Professor Herbert Kim Lyerly, who is working on cancer vaccine technology at Duke University, stated: "We are leveraging the known genetic evolution of cancer." His team plans to trial an mRNA vaccine next year in patients with late-stage breast cancer, where tumors typically evolve to become unresponsive to drugs by acquiring mutations in specific genes. Again, the advantage of mRNA lies in its ability to target multiple goals at once, in this case, a handful of potential mutations. Lyerly noted: "There is no better surgeon in the world than your immune system to catch those mutated cells at an early stage." If the initial applications are successful, it could extend patient lifespans by keeping cancer at bay for 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 accounts for up to a quarter of cancer cases.
### Malaria
In October, the World Health Organization approved the launch of the first malaria vaccine. However, there is room for improvement, as the RTS,S vaccine only reduces severe malaria cases by 30%. The primary challenge is that the malaria parasite has developed a method to prevent immune memory. Even after contracting malaria, and despite vaccination, people remain susceptible to reinfection, with the disease killing 500,000 people annually, most of whom are infants and children. In 2012, Professor Richard Bucala from Yale School of Medicine and his colleagues discovered that malaria caused "immune memory loss" using a protein called PMIF, which kills memory T cells. Bucala is working on an mRNA vaccine that would immunize against PMIF. Studies conducted on mice suggest that blocking the protein allows the immune system to clear malaria faster, leading to milder disease and, importantly, future immunity. Bucala has partnered with scientists at the Jenner Institute in Oxford to test the candidate vaccine, and if results are positive, they hope to start human trials next year. Bucala stated: "There is an urgent need for vaccines in the developing world for parasitic diseases that have long inhibited the economic and social development of many countries." He added: "mRNA has not only enabled the success of the PMIF vaccine, but the platform is also much cheaper than protein-based vaccines, which opens up opportunities for malaria vaccines that were previously non-existent."
### Acquired Immune Deficiency Syndrome (HIV)
Derek Cain from the Duke Human Vaccine Institute said: "We are now entering the fifth decade of a global HIV epidemic." So far, a vaccine has remained elusive. Cain's team has focused on a subset of HIV patients (less than a third) who ultimately develop specialized antibodies that can neutralize HIV years after infection. By this time, a massive reservoir of the virus has built up in the body, making it too late to eliminate the infection. Cain remarked: "It’s like you found a fire extinguisher but the whole house is already on fire." Conversely, if a vaccine could stimulate these antibodies, the hope is that they could clear HIV before it becomes entrenched. Cain and his colleagues have meticulously mapped out the winding path the immune system takes to generate these highly specialized antibodies, and as part of a consortium, they are developing a series of four or five multi-target mRNA vaccines designed "to recreate the arms race between the immune system and pathogens." Cain added: "We do not expect it to work at 100% or 90% like COVID-19 vaccines, but even if we can reach 50-60%, that would be successful; 70% would be remarkable."
