vaccine strategies against SARS-CoV-2

… an overview …

Currently, numerous trials are under way globally to obtain a vaccine against SARS-CoV-2. As of June, there are 13 candidate vaccines undergoing first clinical trials, a further 126 candidates are in preclinical examination (WHO, June 9, 2020).

Four aspects are important in the current vaccine race:

  1. The vaccine needs to be immunogenic enough to provide protection from infection with SARS-CoV-2; this is the prerequisite, without this, a vaccine makes no sense. It is not sufficient to protect from the diseases since the virus is spread before onset of disease.
  2. Safety from undesirable side effects needs to be guaranteed. Current vaccines may result in severe side effects in one in a million cases. Should this number go up tenfold, this would mean in billions of vaccines, thousands of severe side effects. Thus, the vaccine needs to be vigorously tested. With such a huge number of vaccinations, a risk is not acceptable. Such tests, however, require a large number of volunteers and a long time, which has direct implications for the following point 3!
  3. During an ongoing pandemic, time is crucial: The vaccine should be available ASAP. The basic development of a vaccine may take a few months. Then, however, it needs to be tested, first for safety, followed by efficacy tests.
  4. Finally, there need to be enough doses to vaccinate billions of people worldwide. Thus, large facilities are needed. Different vaccines (see below) do require different production processes. Only after approval the vaccine may be administered. In order to safe time, financially strong companies might start production ahead of approval, to quickly distribute the vaccine once it is licensed. This, however, is risky: Without approval, the investment is lost.

What are the principles the current SARS-CoV-2 vaccines are developed on?

Vaccines may consist of whole viruses or parts of them.

1. Inactivated viruses might be the oldest method. Consequently, there is a lot of experience. Its advantage is the speed of development. The virus needs to be replicated to great numbers, after which it is inactivated: The virus particles are modified in a way that they lose their ability to replicate. In most cases, this is accomplished by chemicals that either destroy the nucleic acids (the viral genome) or the enzymes needed for replication. The surface molecules need to stay intact, since they are responsible for the antibody production. Should the surface molecules be changed in any way, the antibody response may be botched. Another disadvantage is the tendency to produce antibodies but no real T-cell response, which is important for long term immunity.

2. Attenuated viruses are replicating viruses, that have a reduced replication – and thus disease inducing – capacity. They are infectious, but the immune system has enough time to inactivate them. They replicate in slow motion, while the immune system works in real time. Decades ago, attenuation was accomplished by cultivating the viruses in non-human cells. During passages in these cells, the virus over time adjusted to the new organism, while losing the ability to efficiently replicate in humans. This process could take years. Nowadays there are molecular methods to achieve an attenuation much faster. The viral genome is being changed, while the protein structure (and hence immunogenicity) stays the same.

There is one obvious drawback: The virus may in theory undergo the same procedure in reverse and readjust to the human organism. Therefore, such a vaccine needs to undergo rigorous tests to see if such a process is to be expected. This may take years.

3. A modern method is using so-called viral vectors. These are viruses, that do not produce a disease or just a weak one. They are being manipulated to contain bits and pieces of the virus you want to vaccinate against. Thus, they are presenting SARS-CoV-2 proteins to the immune system, leading to antibody response. These vectors come in two flavors: Replicating or non-replicating. The replicating ones are being inactivated by the immune system in a short time.

One disadvantage is a possible existing immunity against the carrier-virus; i.e. the person being vaccinated had come into contact with this virus before.

As with all other vaccines based on viral fragments, it all depends on immunogenicity and if a robust T-cell response is being achieved.

4. Recombinant proteins are another method. In that case, specific viral proteins are being produced in cell cultures, followed by extraction. Combined with a proper formulation, they are injected. Immune cells patrolling the periphery are taking up these proteins to present them to other immune cells, leading to an immune response.

Again, mostly antibodies are being produced, with little T-cell response, leading to a short-term immunity.

5. DNA vaccines are based upon DNA molecules carrying DNA-copies of SARS-CoV-2 parts (coronaviruses are RNA-viruses). They are being injected and need to find their way into cells, which is accomplished by several tricks. The cell then produces mRNA-copies of the intruder, followed by proteins that mimic an infection. This again results in antibody-production and T-cell activation.

6. mRNA vaccines are the latest of these developments. They are based upon messenger RNA, which directly transfers information to the cellular protein production machinery. To that end, the appropriate parts of SARS-CoV-2 RNA are stitched into mRNA molecules, packaged into lipid vesicles, and injected. Cells are taking up these vesicles and will produce proteins mimicking an infection. Consequently, T-cells and antibodies are produced in great numbers. This method may be developed pretty fast and scaled up efficiently.

Companies working on this method are Moderna, CureVac and BioNTech.

One disadvantage of this method is the issue with RNA: RNA is notoriously unstable. It needs to be handled accordingly. Currently, there is a lack of experience with this kind of vaccination.

What kinds of vaccine are being developed against SARS-CoV-2?

Currently in clinical tests there are vaccines based upon inactivated viruses, protein subunits, non-replicating viral vectors, DNA, and RNA. Among the 126 candidates that are in pre-clinical evaluation, additionally there are attenuated viruses, replicating vectors, and virus-like particles (VLP).

7 of 13 clinical tests are dealing with novel systems (vectors at Oxford University/AstraZeneca and CanSino; mRNA vaccines at Moderna and BioNTech/Fosun/Pfizer).These techonolgies are very promising, however, there has been no approved vaccine on their basis yet.

Common to all vaccine strategies is the fact, that there is no guarantee for a successful vaccine against SARS-CoV-2. There are a number of viruses that cannot be vaccinated against, even after decades of trying.

The upcoming months will show. A first positive result was communicated from China. An inactivated virus provided protection in monkeys, a small number of animals, however: A real progress will take the course of this year.

The large number of clinical and preclinical assays and the number of different methods in a global competition is providing some hope that the one or other assay will succeed. We are being kept in suspense.

Consequently, alternatives to vaccines need to be followed, such as the search for drugs providing treatment or prophylaxis. Should all vaccine strategies fail in the foreseeable future, medication would provide the only way to control the virus globally. We consider it uncertain and a high risk to concentrate on vaccine development, exclusively.

sajo is providing its high technology, which offers the opportunity to identify and isolate highly active antiviral substances to compile an antiviral portfolio with broad applications.

We are observing with some concern that the German government is giving € 400 M to two companies, the both of which are concentrating on vaccine development with the same technology: This is a hazardous gambling with taxpayers’ money.

Stay informed and particularly, form your opinion on this topic.

Sabine and Joerg