Abstract
The greatest scientific advance to come out of the coronavirus disease 2019 (COVID-19) pandemic was arguably the approval of mRNA vaccines for use in humans. By now, billions of people around the world have received mRNA vaccines that provide short-term protection from infection and long-term protection from severe disease. Three years ago, most people had never heard of an RNA vaccine, and no one expected to be soon receiving an RNA vaccine for a virus that we did not yet know existed.
The rapid development of these vaccines was astounding in and of itself, but the fact that this was achieved using a platform never employed before in humans was even more unanticipated. Fast forward 3 years, and we now find ourselves wondering how many diseases might someday be managed using RNA-based strategies.
Over 20 years ago, immunization with a self-replicating RNA vector was shown to protect mice from tumor challenge. Before 2020, we saw ∼30 scientific publications each year on the topic of RNA vaccines. Of course, these numbers climbed to >1,000 in 2021, and will likely hit 2,000 before 2022 is over. Even before RNA vaccine research, DNA vaccines were intensely pursued. The “gene gun” was a captivating term that was frequently heard within the realms of vaccinology as well as gene therapy, but unfortunately, neither of these platforms was making it beyond very successful proof of principle studies in animals. Of course, desperate times call for desperate measures.
By now, billions of doses of mRNA vaccines have been administered to humans. The impressive safety profile of these RNA-based vaccines has provided proof that we can safely and effectively administer RNA into humans for the prevention, and potentially the treatment, of many diseases. The immediate extensions of this technology could lead to new vaccines targeting pathogens for which we already have effective vaccines, such as influenza A virus (IAV). The short process of mRNA production has already demonstrated its utility and adaptability through the rapid updating of COVID-19 vaccines designed to match recently emerging Omicron subvariants.
A similar strategy could be applied to the development of improved IAV vaccines that could theoretically contain more than three subtypes and potentially more than two different genome segments. Of course, dosage would be key here because we do not know yet how many copies of a given RNA are sufficient to generate enough protein to stimulate an efficient immune response.
Other viruses have been notoriously challenging for vaccine design. Human immunodeficiency virus (HIV) and hepatitis C virus (HCV), as examples, are extremely variable, and elicit strong immune responses upon infection. So a vaccine that could prevent establishment of chronic infection with either of these viruses would need to induce an even more effective immune response than that which normally occurs during natural infection with either of these viruses. It is unlikely that a clonal mRNA vaccine will do any better than any other vaccine platform that has proven ineffective against the HIV or HCV, but given the increased capacity of mRNA vaccines to potentially include mRNAs coding for multiple proteins representing numerous clades or genotypes, it might work.
Another important concept highlighted by the current pandemic is the notion that a vaccine does not need to be highly sterilizing to be beneficial. Of course, we would all like to see higher levels of protection from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for longer durations, but in the middle of a pandemic that was killing thousands daily, a vaccine that reduced severity of disease was of immense benefit to public health and society. Better COVID-19 vaccines are indeed needed going forward, and it will be interesting to see whether multivalent mRNA vaccines containing multiple SARS-CoV-2 genes will provide better and/or longer protection from actual infection.
Now, if we consider HIV and HCV again, even if we never manage to make an effective vaccine that prevents infection, could we perhaps have an RNA-based long-acting therapeutic vaccine that could be injected a few times a year that could slow or prevent disease progression? Could such an RNA-based therapeutic vaccine result in HIV-infected individuals not getting immunocompromised even in the absence of antiretroviral therapy, or perhaps HCV-infected individuals would not progress to cirrhosis and fibrosis even when they do not have access to curative direct-acting antiviral therapy? It is exciting to consider such possibilities.
If we step outside the viral immunology field for a moment, one can also envision many other diseases potentially being managed by RNA-based approaches. Great strides have been made in recent years in the oncolytic viruses field where we have seen specific targeting of viruses to kill cancer cells. Along the same lines, mRNA therapies might soon be applied to the treatment of cancer. For example, RNA encoding anticancer proteins could be injected directly into solid tumors to effectively kill the cancer from the inside. The main pitfall with such a strategy would be containing the mRNA and its protein product within the tumor. One way around this might be to use mRNA approaches that instead flag the cancer cells for attack by the immune system by delivering mRNA coding for immune activation markers or checkpoint inhibitor-like proteins that would stimulate anticancer immune attack.
In a broader sense, in genetic diseases for which a specific mutation is responsible for a pathogenic phenotype, for example in cystic fibrosis, Huntington's disease, sickle-cell anemia, and many congenital immunodeficiencies, mRNA-based delivery of the proper gene sequence could result in restoration of function. Of course, this will not be nearly as easy as it sounds because such therapy will require lifelong administration. The question is how often would affected individuals need to receive RNA injections?
Perhaps at that point, modifications can be made to slow down the degradation of the RNA, or a slow-release/long-acting approach could be developed? All of these options would need to be studied thoroughly for safety and side effects if the goal will be prolonged presence of the RNA in the body, but again, it is intriguing to consider the endless possibilities.
In closing, despite a level of antiscience that has not been seen in centuries, immunology and virology researchers, and science in general, continue to rise to the challenge and maintain a fight against current and new disease threats. We are living and doing research in a time that will be discussed for decades to come, and it is impossible not to be optimistic when we think about what discoveries will be made in the next 50 years. Once again, I sincerely thank all authors, reviewers, and study subjects for their contributions to the work we have the privilege to publish in Viral Immunology.