This is the first episode of our podcast series. In today’s episode we will be discussing what a recombinant protein vaccine is with Antonio Barreiro, HIPRA Human Health Project Leader Researcher.

• What exactly is a recombinant protein vaccine?

All vaccines are based on administering a combination of substances to the person receiving the vaccine, to induce an immune system response that invokes protection against infection by the targeted pathogen, usually a virus or bacteria, so that the person does not contract the disease or has a reduced degree of disease.  

The difference between vaccines directed against the same pathogen lies in the type of substances that are part of the compound [ABV1] used to induce the immune response in the vaccinated person. This includes the antigen, the key element that stimulates protection against a particular disease.

• Tell us more about the antigen, what is it?

The antigen is the part of the pathogen capable of triggering the activation of the immune system of the vaccinated person. It can come from a variety of sources. For example, it can be the inactivated or attenuated pathogen itself. Alternatively, key parts of the pathogen can be used, usually proteins from its surface. The antigen provides the necessary information so that, once inoculated, the cells of the immune system induce an immune response that will protect the person in case of contact with the pathogen. The final goal is to prevent the development of the disease or significantly reduce its severity.

• What type of antigen is used in recombinant protein vaccines?

In recombinant protein vaccines, the antigen used to induce the response of the immune system of the person receiving the vaccine are proteins of the pathogen, or part of these proteins, which are produced in the laboratory. In the case of the SARS-CoV-2 virus causing COVID-19, the main protein involved in the infection process is the Spike protein, located on the virus's surface. It is therefore the main candidate for vaccine design. Recombinant proteins are produced on a large scale by cells that are widely used in biotechnology for the manufacture of drugs of biological origin, and then purified to ensure their efficacy and safety. To get the cultivated cells to produce the desired protein, they are genetically modified to provide them with the information to produce the product of interest. What is administered with the vaccine is small amounts of this purified protein, which is usually accompanied by the adjuvant to enhance the immune system's response.

• Can recombinant protein vaccines transmit the disease for which they vaccinate?

No. These vaccines are produced by cells that are completely free of the virus against which the vaccine is produced. In addition, they only contain one or part of the virus protein and have no ability to infect the cells of the person receiving the vaccine or to generate the symptoms associated with the infection.

• How many antigens can a recombinant vaccine carry?

In some cases the vaccine may carry more than one associated antigen, especially when this is a fragment of a protein, so that the immune system of the person receiving the vaccine will be able to recognise more proteins of the pathogen, or more parts of the same protein. Proteins from different variants or strains of the same virus can also be combined, thus broadening the spectrum of protection and maximising the possibility of recognising and neutralizing it. .In some cases, proteins with more than one antigen in the same structure are synthesised, which can help to enhance the immune response against these antigens.

In both cases, these are referred to as multivalent vaccines. Specifically, vaccines containing 2 antigens are known as bivalent.

• What is the adjuvant?

An adjuvant is a substance that boosts the immune response of a vaccine. There are different types of adjuvants and they are administered together with the recombinant protein of the vaccine, as it is usually not sufficient on its own to generate a strong immune system response to protect the person being vaccinated. The purpose of the adjuvant is to promote and enhance the activation of the immune system of the vaccinated person, allowing a stronger response [ABV1] and invoking better protection against the virus or pathogen. Also, the adjuvant can protect and stabilise the antigen during the vaccine storage, preserving its properties.

• Now we know what recombinant protein vaccines are, but how do they  work?

As mentioned previously, the aim of a recombinant protein vaccine, and vaccines in general, is to provide the person receiving the vaccine with protection against future infection by the pathogen to which the vaccine is addressed. To achieve this, the vaccine aims to generate an immune system response similar to the natural response which would occur if we were infected with the pathogen, but without developing the symptoms and disease that would normally be triggered by infection with the patheogen. In this way, the immune system of the person being vaccinated acquires what is known as recall immunity against the pathogen. This consists of a variety of response mechanisms that will be activated when the person comes in contact with the pathogen, which will prevent us from becoming infected or, if we do become infected, the symptoms and disease developed by the pathogen will be much milder.

• Tell us more about what immunological memory is and how we get it.

The immunological memory is a complex process in which different processes of the organism are involved simultaneously, but I will try to simplify it and make it understandable:

When a pathogen encounters our immune system for the first time, the first responder is innate immunity. In the same way, when the first dose of a vaccine is administered, this is also the first part of the immune system that is activated in response to the antigen and enhanced by the presence of the adjuvant.

Innate[ABV1]  immunity is the first line of defence after the initial infection, it acts quickly, is non-specific and does not generate memory, but it is the basis for acquiring the sought-after immune memory that will protect us against the pathogen. At this early stage, specific cells involved in innate immunity capture and present the antigen, and at the same time they activate other cells of the immune system responsible for an immediate response against the pathogen and inflammation (they are partly responsible for the local response at the site of vaccine administration). On the other hand, these antigen-presenting cells are responsible for activating the so-called adaptive immunity that is the key to the usefulness of a vaccine.

• What is adaptive immunity?

Adaptive immunity is a slower response and generates a long-term defence, is specific and has memory. Once developed, when presented with a pathogen, it remembers whether it has seen it before and, if so, responds more quickly. In response to the activation of adaptive immunity, on the one hand, specific antibodies are generated against the antigen that help fight the pathogen and prevent infection and/or spread of the pathogen. On the other hand, adaptive immunity generates a group of cells that remain in the body and retain the information necessary to recognise and respond to the pathogen. And this group of cells forms the immunological memory that will allow our body to respond more quickly and effectively against the pathogen in the long term, preventing the infection or the harmful symptoms characteristic of the disease.

• So, what determines the usefulness of a recombinant protein vaccine?

There are several aspects.

One: it has to be specific for the pathogen for which it is designed, but at the same time with sufficient disparity to recognise small variations in the pathogen over time.

Two: it has to induce an adaptive immune response with a good level of neutralising antibodies that recognise the pathogen and protect against infection or severe disease.

Three: It is also important to generate sufficient immunological memory to ensure efficient long-term protection, so that frequent vaccinations are not necessary.

This podcast is part of the "RBDCOV Talks" project, a series of episodes where leading scientists, researchers, medical professionals and advocates from the RBDCOV community address the most relevant aspects of clinical trials of vaccines. RBDCOV is a European project funded by the Horizon Europe programme that aims to test the efficacy, tolerability and safety of Bimervax®, the vaccine for COVID-19 developed by HIPRA.