SARS-CoV-2 / COVID-19

With a vaccination, the immune system is trained to recognise pathogens and render them harmless. For this purpose, the pathogen is weakened, inactivated or only individual components of the pathogen are used. In this way, the immune system generates antibodies and T-cells that neutralise the pathogen, kill infected cells and forms an immune memory. In the event of renewed contact with the pathogen, the body can quickly recall the immune memory and fight off the infection.

For effective protection, vaccines should target multiple cell types in the immune system: Antibody-producing B cells and cytotoxic T cells that kill infected cells. Prof Carlos A. Guzmán, head of the department "Vaccinology and Applied Microbiology" at HZI, highlights another aspect:

For an effective vaccination, you have to stimulate T-helper cells in parallel. This is the only way to get effective antibodies, and to form an immunological memory that induces the production of these very antibodies in the event of an infection.

Prof Carlos a. Guzmán, HEAD OF THE DEPARTMENT OF VACCINOLOGY AND APPLIED MICROBIOLOGY

The currently valid recommendations of the Standing Commission on Vaccination (STIKO) for basic immunization and booster vaccinations can be found on the STIKO website.

The structures of the pathogen that the immune system recognises are called antigens. From research on the SARS and MERS coronaviruses, it is known that antibodies that neutralise the spike protein on the surface of the virus prevent infection. Coronaviruses use the spike protein to bind to a receptor on the surface of the host cell and enter the cell.

Most vaccines against SARS-CoV-2 rely on the spike protein as a vaccine antigen. They differ in the way the spike protein enters the body.

The first two vaccines against SARS-CoV-2 to be granted conditional marketing authorisation by the European Medicines Agency (EMA) are the mRNA vaccines from BioNTech & Pfizer (Comirnaty) and Moderna (Spikevax). Unlike traditional vaccines, this technology does not directly administer the vaccine antigen. Instead, the vaccine contains the blueprint in the form of single-stranded RNA packaged in lipid nanoparticles. The blueprint in the corona vaccines encodes the spike protein on the surface of the virus.

This messenger RNA (mRNA) is translated into proteins in the cytoplasm. Some of the spike proteins produced in cells are shown on the cell surface by antigen-presenting cells and recognised as foreign by other immune cells. This triggers an immune response that produces antibodies and cytotoxic T cells specifically directed against the coronavirus.

The vaccine mRNA, lipid nanoparticles and spike proteins are degraded by the body within a short time. However, the antibodies and spike-reactive immune cells are active for a longer period of time. Prof. Carlos A. Guzmán dispels concerns about the safety of mRNA vaccines in terms of promoting modifications of the human genome:

The RNA vaccine has barely a chance of changing our genome. In extremely few cell types and situations (e.g. germ cells), there are genetic elements that encode the enzyme reverse transcriptase. This enzyme is able to transcribe mRNA into cDNA, so while it is theoretically possible for an mRNA produced by the same cell (and there are hundreds of thousands of these) or mRNA introduced from outside to be transcribed into cDNA, this system works with incredibly poor efficiency. However, in the cells into which the mRNA enters through vaccination, these processes usually do not take place. It is also a fact that the mechanisms addressed already take place in the absence of the vaccine and an mRNA vaccine cannot influence such mechanisms.

PROF CARLOS A. GUZMÁN, HEAD OF THE DEPARTMENT OF VACCINOLOGY AND APPLIED MICROBIOLOGY

The Helmholtz Association's "Klar soweit?" comic also explains how RNA vaccinations work (only in German).

Vector vaccines and mRNA vaccines share the basic principle of eliciting a defence response without administering a pathogen or even a part of it. Rather, they get the body to produce the crucial antigen itself. Thanks to the "programmability" of the genetic information in the vaccines, they can be adapted relatively quickly when the virus changes. For example, mRNA vaccines adapted to the Omicron variant were approved for booster vaccinations in the autumn of 2022.

Unlike mRNA and vector vaccines, which deliver the blueprint for the vaccine antigen, protein-based vaccines already contain the antigen. In December 2021, the first SARS-CoV-2 vaccine with this mode of action received the EMA authorisation. This is the vaccine from the company Novavax (Nuvaxovid). For production, the gene that codes for the spike protein is introduced into insect cells with the help of a virus. These cells produce large quantities of the protein, which forms synthetic nanoparticles after purification.

Overall, the immune response triggered by protein-based vaccines is weaker than with other technologies. To stimulate the immune system comprehensively, they usually contain adjuvants. The Novavax vaccine has saponins added, which are extracted from a soap tree.

Protein-based vaccines have a good safety profile and can be stored at refrigerator temperatures, but they are comparatively expensive to produce. Prof Carlos Guzmán comments:

“Protein-based vaccines are very well known, are usually better tolerated, and there are no major open questions. One disadvantage is that protein-based vaccines take longer to develop than vector or mRNA vaccines.”

PROF CARLOS A. GUZMÁN, HEAD OF THE DEPARTMENT OF VACCINOLOGY AND APPLIED MICROBIOLOGY

In particular, mRNA-based vaccines can be more easily adapted to new virus variants. How effective the vaccine is against new SARS-CoV-2 variants such as Omikron and whether adaptations will be necessary is not yet known at the time of approval.

This infographic also explains the mode of action of protein-based vaccines.

Vaccines based on inactivated viruses were historically called killed vaccines to distinguish them from live vaccines that were attenuated but capable of replication. The inactivated whole virus vaccine from Valneva (trade name VLA2001) is a “classic” killed vaccine according to this definition. However, the mRNA-, vector- and protein-based vaccines against SARS-CoV-2 do not contain replicating agents either.

VLA2001 contains purified and chemically inactivated virus particles. These are propagated in the Vero cell line and subsequently purified. In contrast to the previously approved mRNA, vector and protein vaccines, not only one viral antigen (spike) is vaccinated, but various SARS-CoV-2 antigens. This is intended to trigger a broader immune response. In addition, the vaccine contains aluminium salt and a short synthetic DNA fragment (CpG oligonucleotide 1018) as adjuvants. This is necessary to promote the T-cell response, which is often weaker with inactivated vaccines than with live vaccines. The vaccine can be stored at refrigerator temperatures for several months.

Prof. Carlos A. Guzmán's department is researching a vaccine against SARS-CoV-2 that can be administered via the mucous membranes, thereby conferring superior protection against virus infection and transmission. Instead of being injected into the upper arm, the vaccine could be administered by nasal spray. An adjuvant developed at the HZI is used in this project. The adjuvant c-di-AMP enhances the immune system's reaction to the vaccine.

As with the already approved vaccines against SARS-CoV-2, the spike protein on the viral envelope serves as an antigen against which an immune response is generated. The researchers are focusing on a vaccine that contains a biotechnologically produced spike protein (subunit vaccine). This type of vaccine is already established and can also be used safely in immunocompromised individuals.

In addition, the scientists are using bioinformatics approaches to search for synthetic variants of the spike protein that lead to the formation of cross-reactive immune responses. The aim of this project is to ensure that vaccination with the synthetic spike protein also protects against variants of SARS-CoV-2 as well as against other and upcoming coronaviruses.

In cooperation with the GSI Helmholtzzentrum für Schwerionenforschung, HZI researchers are working on improved methods for inactivating viruses for vaccine research. The inactivation of viruses by heat or gamma radiation is a traditional approach for the production of inactivated vaccines. However, this can damage the surface and membrane structures of the viruses, which has a negative impact on the immunogenic effect of the vaccine. The GSI and HZI are now investigating whether radiation with high-energy heavy ions can inactivate SARS-CoV-2 while largely preserving the virus structures.

In the context of the European Commission funded Transvac 2 Consortium (A European Network of Vaccine Research and Development) the Team of Prof. Carlos Guzmán also supports the development of other COVID-19 vaccines by providing services to biotech companies and academic groups.

As with all vaccinations, reactions can occur shortly after administration. These are caused by the activation of the immune system. "With vaccines based on mRNA or with vectors like adenoviruses, about half of those vaccinated have local or systemic non-serious side effects, such as chills, headache, fatigue or pain at the injection site. This is a much higher proportion than with many established vaccines. Nevertheless, according to all that is known so far, the vaccines are as safe as other vaccines, and the risk-benefit balance is adequate for the populations for which the vaccines have been approved.

PROF CARLOS A. GUZMÁN, HEAD OF THE DEPARTMENT OF VACCINOLOGY AND APPLIED MICROBIOLOGY

In Germany, the Paul Ehrlich Institute monitors the safety of vaccines. It collects and evaluates reports on suspected cases of adverse reactions and regularly publishes safety reports.

Paul Ehrlich Institute: Frequently asked questions on SARS-CoV-2 vaccines
European Medicines Agency (EMA): COVID-19 vaccines key facts
European Commission: Information of the safety of Covid-19 vaccines
Interview with HZI researcher Prof Luka Cicin-Sain: Getting a flu shot and the Corona booster: Does it make sense?
Max Delbrück Center for Molecular Medicine: How the vaccines fight coronavirus
Wellcome Trust: Four reasons why we need multiple vaccines for Covid-19​​​​​​​