Universal Vaccine – How Synthetic Biology is charting the path.

The history of vaccines is older than is usually thought. There is written evidence showing primitive vaccination during the 10th century in China, during the Liao dynasty. This remedy against smallpox consisted of pulverizing dried cow pustules and applying them to a wound inflicted on the patient.

It should be noted that this was long before the discovery of the microscopic and molecular principles of the disease and of human immunity. Since then, many discoveries have been made thanks to human ingenuity and the collaborative effort of science. Vaccines are now easily mass-producible and much more effective in preventing infectious diseases.

There are many types, based on antigens, genomic modifications of existing viruses or even mRNA. We could say that the sophistication of this technology is at an all-time high due to the public and private investment caused by the pandemic we are currently experiencing. However, there is one drawback that is of great concern, since the immunity-generating capacity of vaccines will depend on the exposure to the pathogen and its evolutionary ratio. Neither influenza nor SARS-CoV-2 are stable agents, so we would need to update vaccine information from time to time.

Why is this happening?

The explanation is well known, although sometimes misunderstood. Evolution plays a fundamental role in biological adaptation under adverse conditions. Consider what happens when we get vaccinated. Harmless foreign bodies, usually peptides, interact with immunity through various mechanisms (e.g. antigen presenting cells – dendritic cells). It is this immune reaction itself that can cause fever, pain, or inflammation, and not infection by a pathogen. After this immune reaction, memory B cells make and store in their genome a version of the antibodies needed for a particular epitope or region of the antigen. There are five types of antibodies, with different properties; although all act as opsonins, facilitating phagocytosis of a pathogen if it comes into contact with these regions again.

From the point of view of SARS-CoV-2, for example, if suddenly the whole population starts to generate a targeted response, the evolutionary process is accelerated by what is known as a Bottleneck. Moreover, in cases where the pathogen has global exposure, gene drift and founder effect are very apparent, further accelerating the existence of versions or variants of the same virus in a short time. It should be remembered that in the case of RNA viruses, this is even faster because they sacrifice individual stability in pursuit of greater population adaptability.

Is it necessary to generate a renewed immunity?

Evolution works for all of nature, and our immune system is one of the most evolutionary events in the animal kingdom. Therefore, there is a natural solution to this problem. When making antibodies to a particular antigen, there is a hypervariable region at the ends of the antibodies, which generates virtually random short sequences, thus producing a battery of slightly different antibodies to the same antigen. This manages to reduce the "evolutionary noise" or "antigenic drift" present in pathogens. The problem is when these differences become more pronounced in short periods of time, as seems likely to happen with SARS-CoV-2 and is already occurring with influenza. How can synthetic biology build a durable vaccine? Is this even biologically possible?

Universal Vaccine – What it is?

A universal vaccine is defined as a vaccine that is capable of generating long-lasting immunity against all versions of the same virus. The main problem for this to become a reality is that it depends not only on human immunity but also on the evolutionary history of the virus itself. We label every organism on earth with a first and last name, but variability is not a discrete quality, but a continuous one. In fact, there are virtually infinite varieties of each virus that we call SARS-CoV-2 or H1N1. Many of these "infinite" possibilities are non-viable or defective for infection, while others are more virulent, which is what is normally selected for by evolution, and is what we are currently witnessing. This makes it virtually impossible to generate an effective vaccine against so many unpredictable changes in a multitude of locations simultaneously, all with their own viral haplotype.

However, as with all biological systems, there are ways to deal with the problems that arise. Targeting immunity to more evolutionarily preserved antigens, which do not change as much or at all over time (because they are indispensable for the molecular integrity of the virus and do not depend on the host) could have a much greater range of immunity. This is called "universal antigen” and finding it would be great at this time in the face of a pandemic of a virus that has been shown to be able to diversify successfully in very different populations.

Current Research & Start-ups

Osivax is a company whose goal is to find this universal antigen for influenza and to "vaccinate" T cells by improving antigenic presentation. GPN Vaccines opts for a rather ingenious approach, what they call a "whole cell vaccine". In this case, it is not a virus but a bacterium, S. Pneumoniae, whose virulent content is eliminated by gamma rays. This is clever because the variety of antigens in a whole cell confers very powerful robustness to the antibodies' ability to detect a different strain of that bacterium. Even if one or more antigens change through evolutionary drift, most antigens will certainly remain stable.

There are a whole set of initiatives, all of which are based on these two principles - the search for a universal antigen or the inoculation of a library of diverse antigens that provide a catalog defining the species over many years.

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