While countries around the world are fighting Covid-19 and the further spread of the coronavirus pandemic, scientists are intensely looking for a vaccine against Sars-CoV-2. But which approach promises the best success is still unclear. The most advanced are novel mRNA vaccines that cause the cells to generate the immunostimulating virus antigen themselves. A first study has just started in the USA. However, this type of vaccine is still completely untested. Other teams are therefore taking a more classic approach to the virus.
So far there is no approved remedy or vaccination against the new pathogen Sars-CoV-2. In China and the United States, however, clinical trials are already underway with active substances that prevent the virus from multiplying and are thus intended to prevent severe courses of Covid-19. One candidate is Remdesivir, which was originally developed against Ebola. Its use is now being tested in Germany in tests with patients. But in addition to the acute treatment of sick patients, it is also about permanently stopping the coronavirus pandemic with a vaccine. Because epidemiologists currently fear that the current outbreak will only weaken slightly in the warmer season and that a new wave of infection could be imminent in autumn. That is why research teams around the world are working on the development of a vaccine against Sars-CoV-2. Before infection, it is supposed to enable the body’s immune system to recognize the pathogen and to build up a defense against it.
In the case of the corona virus, current strategies primarily use proteins from the virus envelope and the spike protein required for binding to human cells as a “virus identifier” – technically known as antigen. The way in which the immune system receives this preliminary information about the virus differs among the vaccine candidates currently being tested. In the classic approach, a vaccine typically contains killed viruses, viral proteins or harmless viruses with planted corona coat proteins as the antigen. They then trigger the immune response and the formation of antibodies directly. So far, this vaccination strategy has been used for most vaccinations, for example against seasonal flu or measles. Several research teams and companies are currently using this approach. The starting point is usually already developed vaccines against influenza, Sars, Mers-CoV or the infectious bronchitis virus (IBV). Using genetic engineering, their carrier viruses are modified so that they now carry envelope or binding proteins from Sars-CoV-2. Researchers at the German Center for Infection Research, at the Israeli MIGAL Research Center, in Great Britain and also at the pharmaceutical company Janssen in the USA are currently developing and testing such a vaccine.
mRNA vaccine: the body makes the antigen itself
However, the new mRNA technology is considered a faster solution. The vaccine does not contain the antigen itself, but only the building instructions for it – in the form of a messenger RNA. The basis for the mRNA sequence is the genetic information of Sars-CoV-2, which was decrypted and published by Chinese researchers in January 2020. The mRNA contained in the vaccine is taken up by the cells and read out in the ribosomes, the protein factories of the cell. These then produce the corresponding viral protein or protein piece and release it in the body. The immune system can then react to this antigen and form corresponding antibodies. The advantage: Because the body itself produces the antigen and you do not have to produce carrier viruses, this vaccine can be produced and modified relatively quickly. This approach is therefore particularly promising and vaccine candidates based on this principle have been the most advanced to date. Current developers of such corona virus vaccines include the German company CureVac, recently courted by Donald Trump, and the US company Moderna.
“With our unique mRNA technology, we can imitate nature and provide the body with the information it needs to fight the virus,” explains Mariola Fotin-Mleczek from CureVac. The company is currently testing ten different versions of an mRNA vaccine against Sars-CoV-2, in which experiments are being carried out primarily on sleeves to protect the RNA from being taken up into the cells and on reinforcing additives. A first clinical trial of an mRNA vaccine against the coronavirus has just started in Seattle. The vaccine mRNA-1273 developed by the US company Moderna contains the building instructions for the configuration of the viral spike protein, which is available before the virus is docked to the cell. The drug is currently being injected into 45 healthy volunteers in two doses 28 days apart. This phase 1 study will initially test whether the vaccine is safe and tolerable. “This study is the first step in the development of an mRNA vaccine against Sars-CoV-2 and we expect important information about safety and immune activity from it,” says Tal Saks from Moderna. If this vaccine candidate turns out to be compatible, a first phase 2 study with Covid patients could follow.
RNA technology is still new territory
But mRNA technology is new territory – there is not a single approved vaccine based on this principle. Initial experience has so far only been obtained from clinical studies, including a Phase 1 study by CureVac with an mRNA-based rabies vaccine and a Phase 2 study by Moderna against the cytomegalovirus. “It is important to emphasize that we are still at the beginning,” Moderna also emphasizes. In order to accelerate the development of the vaccines, the researchers and companies have currently shortened the usual phase of animal testing or are even carrying it out in parallel with the first studies in humans. This should enable the development of a vaccine effective against Covid-19 by the end of the year, but involves considerable risks. One of them: It cannot be clarified in time whether the vaccine does not even worsen the course of the disease in the event of an infection. Then vaccinated people would be even more likely to develop Covid-19 than non-vaccinated people. Such aggravation was observed in 2004, among other things, when testing a Sars vaccine on ferrets.
And another question remains unanswered: whether and how well a once acquired immunity to Sars-CoV-2 protects against a new infection. Because there is not yet enough data from recovered Covid 19 patients. Initial studies with rhesus monkeys in China suggest that a lived-in Covid disease protects against the virus. And this has also been observed with the related viruses Sars and Mers-CoV. But how long this immune protection mediated by antibodies lasts is open. Antibodies against Sars were still detectable in the body of infected people for several years, but with Mers-CoV this immunity waned in the course of a few months. The immune response to the coronaviruses, which are closely related to Sars-CoV-2, seems to be similarly short-lived, which have been circulating in the human population for a long time, but only trigger mild colds, as studies show.
Another problem could be future changes in the coronavirus: If the structure of the pathogen’s envelope or binding proteins changes due to mutations, vaccines that have now been developed could be void in the next pandemic wave. Because most of them only use the spike protein or a part of it as an antigen – and are therefore dependent on these structures remaining the same. However, experiences with seasonal flu and other viruses, among others, show that such coat proteins are not immune to mutations. So far, comparative genetic analyzes of various Sars-CoV-2 have shown little evidence of strong mutability – but that does not mean that the virus will remain the same over the next few months. According to some experts, it may therefore be important to pursue several different vaccine strategies in parallel.
Sources: Nature, CureVac, Moderna, Science, Association of Research Pharmaceutical Companies, Chemistry World, Harvard University