Can we create vaccines that prevent infection from novel viruses that will appear in the future?

In the 21st century, after experiencing SARS-CoV-1, H1N1 influenza, and recently SARS-CoV-2 which caused the COVID pandemic, numerous deaths and severe illness cases occurred. In the case of SARS-CoV-2, vaccine development time was dramatically shortened due to the development of mRNA vaccines, but it still took 11 months. Also, various side effects were reported during the process of shortening clinical trials. Having experienced several pandemics over the past 20 years, questions about the possibility of preventive vaccines that can prepare for future viruses that have not yet emerged have become more importantly highlighted.

Is it possible to create vaccines in advance for viruses that will appear in the future? There are two known strategies for this. The first is to preemptively develop vaccines by accurately predicting what new viruses will appear in the future. The second is to develop vaccines that can have universal effects against multiple viruses with outbreak potential.

For the first prediction strategy, there are several detailed topics, but predicting ‘what mutations will appear within one virus’ is most important. Currently, the viruses of interest are influenza and coronavirus. These two viruses share the common characteristic that they can be easily transmitted because they are respiratory viruses and undergo many mutations. Particularly from a vaccine development perspective, the fact that many mutations occur is more troublesome. Unlike DNA viruses, influenza and coronavirus are RNA viruses, so mutations occur more easily. Among them, influenza particularly experiences a phenomenon called antigenic shift, which occurs when different viruses are co-infected, gene segments mix, and new types of viruses appear as a result. Due to these characteristics, influenza is being mentioned as the most important novel virus that could cause major outbreaks in the future, and prediction of this is recognized as an important task. Related to this, various types of predictions are being attempted through deep learning and computer simulation, but the accuracy of predictions cannot yet be guaranteed.

For the second universal vaccine development strategy, it can be interpreted differently depending on the scope of universality. The difficulty and possibility of universal vaccine development vary depending on whether the scope of universality is considered as various mutations within one type of virus or as multiple types of viruses. The reason universal vaccines are difficult is due to antigen specificity. In acquired immunity where the human body fights against viruses, there are mainly antibodies and T-cells, and antigen specificity plays an important role. One type of antibody or T-cell receptor specifically binds to one viral structure or peptide sequence called an epitope, which is called antigen specificity. Therefore, being able to fight against multiple viruses paradoxically means reduced antigen specificity, inevitably leading to lower effectiveness. In other words, there is a trade-off relationship between universality and effectiveness.

Therefore, comparing the two vaccine development strategies comprehensively, prediction-based vaccine development for future viruses can induce specific and powerful immune responses to corresponding viruses if prediction succeeds, but has the disadvantage that such prediction itself is difficult, while universal vaccines can commonly act against multiple viruses but may have reduced effectiveness.

Another consideration in vaccine development for viruses that have not yet emerged is the harmony between antibody responses and T-cell responses. First, among antibodies that bind to antigens, neutralizing antibodies particularly bind to epitopes mainly involved in viral invasion, such as viral glycoproteins, to inhibit viral infection. This process is called neutralization. On the other hand, T-cells recognize epitopes derived from viral proteins exposed on cell surfaces and kill infected cells to prevent viral proliferation. That is, neutralizing antibodies based on antibody responses perform the role of preventing infection itself, while T-cells cannot prevent infection but can suppress severe illness caused by viral infection. Since vaccines are primarily intended for prevention, the role of neutralizing antibodies seems greater, but there is an obstacle of ‘mutation’ in the role of neutralizing antibodies. Neutralizing antibodies can be easily neutralized if mutations occur in specific narrow epitope parts of viral proteins. In contrast, T-cell receptors have epitopes scattered across various parts of various proteins that one virus has, so they are not easily neutralized even if mutations occur in any one part. However, T-cell-based vaccines kill infected cells after infection to prevent progression to severe illness, so they do not match the meaning of vaccines as prevention.

In summary, for preemptive development of novel virus preventive vaccines, the two strategies for preventive vaccine development mentioned earlier and the advantages and disadvantages of antibodies and T-cells must all be combined according to viral characteristics. Particularly, since viruses experienced by humanity in the 21st century have various mutations, developing vaccines that can elicit not only antibody immune responses but also T-cell immune responses is very important. In current vaccine research, research on platform technologies that deliver antigens is being actively conducted in addition to research on viruses or antigens. Therefore, if prediction of viruses that may emerge in the future and various mechanisms that can induce virus-specific antibodies and T-cells can be delivered more effectively through existing mRNA platforms or new platforms, preemptive development of vaccines that can prevent novel viruses will also become possible.