Will mRNA Vaccines Replace All the Rest?

The success of mRNA vaccines against coronavirus disease 2019 (COVID-19) has stimulated excitement and hope in the fields of virology, immunology, and vaccinology as many now wonder whether viruses we could not defeat in the past with conventional vaccine strategies might now be more vulnerable to the powers of the mRNA vaccine platforms. It is indeed exciting to see new types of vaccines being designed and developed so rapidly, and then to show such great success. Of course, we have much yet to learn about mRNA vaccines with respect to how they actually work, and how they can be improved, but the future promise is undeniable.

At this point it is not clear why mRNA vaccines work so well. The production of the desired proteins inside host cells presumably results in both human leukocyte antigen class I and class II presentation of T cell epitopes, so they obviously stimulate both antibody and T cell responses, but so do viral vector vaccines. Perhaps the RNA has a longer half-life by itself than it would if delivered by a protein or a viral vector that would themselves elicit immune responses? Answers to these questions are beginning to emerge, but the question that most needs to be answered at this point is, why are mRNA vaccines working so well against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? The answer to this question will be the key to finding answers for two other questions: (1) will an mRNA vaccine strategy replace some of the currently successful vaccines? And (2) could an mRNA vaccine work where all other attempts have failed?

To begin to understand why we have been able to make effective vaccines against some viruses, but not against others, we must first examine the targets, the viruses themselves. There is actually a spectrum of complexity with respect to how easy or hard it might be to generate a successful vaccine against a given virus. Exactly where a given virus sits on that vaccinability spectrum depends on many things, but arguably, mostly on how much it likes to mutate. To a nonvirologist, the constant discussion of SARS-CoV-2 variants of interest and variants of concern might give the impression that this new virus mutates faster than any other we have seen, but that is certainly not the case. This notion likely exists in part because for the first time in history, through social media, the general public has real-time access to data on a daily basis regarding how much SARS-CoV-2 is changing, but the fact is, immunologists and virologists have been watching viruses mutate for years, and coronaviruses do not actually mutate as fast as do other viruses, such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV). Nor do they have the superpower that is associated with RNA viruses containing segmented genomes, such as influenza A virus (IAV), which can completely change their outer surface proteins through recombination events as we observed with emergence of H1N1.

On the vaccinability spectrum, we could put viruses such as hepatitis B virus (HBV) on the “easy” side of the spectrum since development of an effective vaccine against HBV required only a single viral protein, with no live component or any accompanying genetic elements contained in the vaccine. That is not, of course, to diminish the value or contribution of years of research and resources that went into understanding HBV and developing vaccines targeting it, but just to say that a safe and simple vaccine approach turned out to be sufficient. Then, on the other end of the vaccinability spectrum, we would have the viruses that are “hard” to develop a vaccine against, such as HIV and HCV. Many factors, including structural masking of antigens and complex envelope glysosylation, can make it difficult to exploit vaccine targets, but arguably, the extreme variability that is inherent to these viruses must be the main barrier to vaccine development.

If we now attempt to place SARS-CoV-2 on this vaccinability spectrum, where does it sit? We know that the SARS-CoV-2 polymerase contains proof-reading ability, meaning this virus does not generate mutations as fast as viruses such as HIV and HCV, which do not contain proof-reading domains in their polymerases and, therefore, generate extreme variability even within a single infected individual. If we then consider that many different vaccine platforms have actually shown success against SARS-CoV-2, we inevitably come to the conclusion that SARS-CoV-2 actually sits closer to the “easy” end of the vaccinability spectrum. Based on that analogy, we cannot assume that mRNA vaccines will be the simple vaccine solution for the viruses at the harder end of the spectrum.

Will mRNA vaccines replace some of the currently used vaccines? Perhaps they will. It seems intuitive that mRNA vaccine technology could be easily adapted to generate IAV vaccines that will work as well or better than current strategies. The most minimal advantage would be the faster production of RNA sequences versus the extra steps involved to make viral proteins. It will be very interesting to determine whether the antigenic load capacity will be higher if numerous RNA sequences can be mixed as opposed to a limited number of actual proteins without falling below a lower limit for elicitation of an effective immune response. So there might indeed be vaccines that could be improved upon by pivoting to an mRNA-based platform. However, the important question from above is the second one, could an mRNA vaccine work where all other attempts have failed? Despite the success of numerous mRNA vaccine platforms, we cannot assume that these will deal any better with the inherent variability in viruses such as HIV or HCV. Will an mRNA vaccine with limited sequence diversity perform any better than any other vaccine platform targeting the same limited number of sequences? The breadth of the quasi-species associated with these viruses will be an equal challenge for mRNA vaccines as it has been for other platforms that have been tried, and unfortunately failed thus far.

In summary, the transfer of mRNA-based vaccine technology to the human species brought on by the COVID-19 pandemic has resulted in a scientific leap that will take years to fully appreciate and understand, which is exciting and is certainly a positive advance. The approval of additional weapons in our arsenal against current and emerging pathogens was badly needed and has been fully welcomed, but we cannot forget that all of these viruses have their own superpowers, and whether or not one type of vaccine will work better than another against a certain virus depends not only on the type of vaccine being used, but also equally on the type of virus being considered, and where that virus sits on the vaccinability spectrum.