New method can reveal how long vaccination remains effective

Disease and treatment 15. jul 2021 3 min Clinical Professor Peter Garred Written by Morten Busch

Vaccination against SARS-CoV-2 has temporarily suppressed the COVID-19 pandemic. However, the new Delta variant and thus the effectiveness and protection of vaccination raises questions about how long the pandemic can be kept at bay. Now, a Danish research team has developed a new and more rapid test that determines whether a person’s antibodies continue to protect them – also against new variants. The test shows that the antibodies formed against a specific part of the virus are far more protective than others. The new test could be an important tool in predicting when vaccination should be boosted.

Becoming acquainted with SARS-CoV-2 has proved to be both unpleasant and surprising for health authorities and populations worldwide. Just when we think the pandemic is under control, new and surprising sides of the virus emerge. With the current mass vaccination proceeding around the world, many experts believe that the danger is over for a while, but on the horizon the question arises as to how long vaccination will be effective and how well it will protect – especially against new variants of SARS-CoV-2.

“We have developed a new test method that can determine very accurately and much more rapidly than existing tests how well our antibodies can neutralize variants of the virus. The test can therefore also determine which types of antibodies are most important in combating the virus and which parts of the virus they counteract. Tests like these can prove to be extremely important both in developing future vaccines, for antibody therapy and especially for monitoring when herd immunity decreases,” says Peter Garred, consultant at the Department of Clinical Immunology, Rigshospitalet and clinical professor, University of Copenhagen.

Easier and faster

COVID-19 rapidly became a pandemic in March 2020. However, the scientific community responded equally fast by developing methods to test and treat COVID-19 and especially vaccinate against the virus. In September 2020, 231 vaccine candidates were in the pipeline and more than 30 in clinical trials. In spring 2021, this enabled mass vaccination, and one in five people worldwide has already been vaccinated once.

“Today we have effective tools to monitor the pandemic, but if we are to be able to combat viruses with vaccination, we need effective tools to measure the actual immune response, meaning whether an individual develops antibodies that can actually neutralize a virus attack. Existing virus neutralization tests, including the plaque reduction neutralisation test, are accurate and good, but they are far too time consuming to use on a large scale. We have therefore strived to develop an equally accurate but less elaborate test,” explains Peter Garred.

The plaque reduction neutralisation test (PRNT) requires waiting to determine whether live SARS-COV-2 form visible plaques in cells or not, whereas the new assay is based on a recombinant technique producing the virus spike protein and the human angiotensin-converting enzyme-2 (ACE-2) receptor. Using these reagents, the researchers have shown that they can mimic whether antibodies in the blood can prevent the virus from infecting our cells.

This is measured using an enzyme-linked immunosorbent assay (ELISA), which is based on a colour change when the spike protein binds to ACE-2. The new antibody neutralisation test correlates very well with the PRNT assay. 

"The test is technically much easier and faster, has much higher capacity and can be automated and is therefore suitable for testing many people. The test has already given the researchers important input about the vaccines. Using the assay in animal experiments, we have been able to show the parts of the spike protein against which antibodies must be formed for a vaccine to be really effective,” says Peter Garred.

Tool for developing future vaccines

When SARS-CoV-2 infects human cells, the spike protein attaches itself to the surface of the cells and then penetrates it. SARS-CoV-2 needs the spike protein and specifically the fragment of protein that binds to the ACE-2 receptor to penetrate the cells. The fact that antibodies that bind to only this fragment of viral protein are the most effective is therefore not surprising.

“However, we were somewhat surprised that the antibodies that linked specifically to the receptor-binding domain were far more effective. This is very important information both for future vaccines but also in developing more antibody-based therapy,” explains Peter Garred.

In the recent waves of the pandemic, antibody-based therapy has proven to be an effective way to ensure far milder disease trajectories among those most likely to develop severe COVID-19. In this therapy, monoclonal antibodies are produced in the laboratory that mimic the process that takes place in the body in forming antibodies in response to infection or vaccination.

“Our experiments show that current antibody-based therapy and vaccination are extremely effective against SARS-CoV-2 in its current form. As the virus mutates, we must expect vaccines and artificial antibodies to adjust, and our experiments indicate which molecular structures in the spike protein developers of both vaccines and antibody-based therapy should focus on in the future,” says Peter Garred.

Finger on the vaccine pulse

“SARS-CoV-2 is currently mutating and creating new and more infectious variants, so measuring the actual effects of vaccines and artificial antibodies against new variants and the effectiveness of newly adjusted vaccines is therefore incredibly important,” explains Peter Garred.

Equally important is monitoring when the current vaccines lose their protective effect among the people vaccinated. Although much of the world expects to be able to develop herd immunity to SARS-CoV-2 during the autumn, this is only part of the answer.

“The immune system requires occasional boosts against various invasive threats – both bacteria and viruses – that surround us, so we expect that we need to be vaccinated again in the future. By regularly measuring the actual immunity of the population, we can now determine when the protective effect of the vaccines wears off and thereby when the next vaccination rounds are needed,” concludes Peter Garred.

“SARS-CoV-2 neutralizing antibody responses towards full-length spike protein and the receptor-binding domain” has been published in the Journal of Immunology, with Rafael Bayarri-Olmos as the first author. The new antibody test has been developed in a non-commercial collaboration funded by the Carlsberg Foundation between Rigshospitalet, the University of Copenhagen, Aarhus University and Novo Nordisk A/S. The Novo Nordisk Foundation awarded Peter Garred a grant of DKK 4,803,750 for the Copenhagen SARS-CoV-2 Antibody Testing Initiative.

Peter Garred leads a research group at Rigshospitalet and the University of Copenhagen. He tries to understand the structure, molecular genetics and c...

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