A scanning electron microscope image showing SARS-CoV-2 (orange), the virus that causes COVID-19, isolated from a patient in the US, emerging from the surface of cells cultured in the lab. Photo and caption: NIAID-RML.
COVID-19 continues to be an immense global challenge, with over 5.2 million confirmed cases and over 338,000 deaths.
In this gloom, science offers hope. Never before have scientists come together to do so much in so little time. Important research that stayed behind paywalls earlier is now openly accessible; over 5,000 articles on preprint servers and over 30,000 viral genome sequences are freely available.
Vaccines against the SARS-CoV-2 virus are also being developed at pandemic speed with 10 candidates in clinical testing and another 114 in pre-clinical development. But the basic understanding of whether a vaccine would work, what might be the correlates of protection, and how would one measure those, has been lacking. This was addressed recently.
Most vaccines in development aim to produce antibodies that would disable the virus from entering target cells. These are produced by B cells. Another arm of immunity utilises T-cells that thwart infection in two ways – the helper T-cells help B-cells produce antibodies, and the killer T-cells seek out and destroy virus-infected cells. But a small fraction of virus-specific B, helper-T and killer-T cells also develop into memory cells, which respond very quickly to future infections by the same pathogen.
The success of most COVID-19 vaccines under development rests on whether they can produce neutralising antibodies. How does one measure these antibodies? How long do these take to develop, and how long do they last?
Researchers from Emory University in Atlanta, USA provide answers to some of these questions in a preprint paper posted on the medRxiv server on May 8. Using molecular biology and biochemical tools they obtained purified receptor binding domain (RBD) of the spike protein, which contacts the ACE2 receptors on target cells to facilitate virus entry (see illustration). Antibodies to RBD are expected to neutralise the virus.
The RBD protein was used to develop blood tests to look for anti-RBD antibodies in COVID-19 patients and assess their ability to neutralise the virus in 44 patients. The study showed that RBD-specific and virus-neutralising antibodies correlated nicely and developed very early after SARS-CoV-2 infection. When validated with 231 hospitalised COVID-19 patients, the RBD-specific antibody test was highly sensitive and specific, and found to be a good surrogate for measuring neutralising antibodies.
“These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines,” said Mehul S. Suthar, co-lead author of the study, in an Emory University press release. “This study provides a snapshot of the immune response as it is happening, not after the battle is over,” he added.
Two recent papers looked at T-cells to SARS-CoV-2. In a paper published May 14, researchers at the La Jolla Institute for Immunology, California, designed peptides (small fragments) corresponding to various SARS-CoV-2 proteins and exposed blood cells from COVID-19 patients to these snippets. Their results showed that all patients carried helper T-cells and over 70% also carried killer T-cells, suggesting that the immune system was “seeing” the virus and mounting a response. These results agreed well with a study from Charité University Hospital, Berlin, posted on medRxiv on April 22.
These and many other T-cell studies are assisted by the Immune Epitope Database and Analysis Resource and the IEDB website, which is the bread and butter of T-cell epitope mapping.
But the real surprise came when blood cells from people who had no SARS-CoV-2 infection were exposed to these peptides. About a third in the Berlin study and about half in the La Jolla study carried the memory T-cells. These are likely to be from past exposure to one of four other human coronaviruses that are endemic and are estimated to cause 20-30% of common cold annually.
“These are comprehensive studies characterising the T-cell response to COVID-19 virus,” says Rafi Ahmed, a leading immunologist and director of the Vaccine Centre at Emory University, Atlanta. “This information will be useful in designing vaccines that induce T cell immunity against COVID-19”, adds Ahmed, who is also a fellow of the US National Academy of Sciences.
Most vaccines under development aim to produce an immune response against the viral spike protein, but the La Jolla study showed the presence of T cells that recognise several other viral proteins. As Ahmed suggests, these studies inform vaccine design by recommending the inclusion of other proteins as well. The whole virus attenuated and killed vaccines may therefore offer better and longer lasting protection compared to single protein vaccines.
“Though T-cells are often overlooked and neutralising antibodies are typically considered a correlate to protection, it is well established that poor T cells result in poor memory B-cells and thus long-lived antibodies – something all vaccine manufactures and proponents of herd immunity are looking for,” says Anmol Chandele, group leader of the ICGEB-Emory Vaccine Programme at the International Centre for Genetic Engineering and Biotechnology, New Delhi.
The blood test developed at Emory University also helps inform vaccine development. Scientists could test the blood of vaccine study participants for the RBD-specific antibodies as a measure of neutralising antibodies, and use it predict vaccine efficacy. The infusion of blood plasma from recovered COVID-19 patients has been proposed as a potential therapy for critical patients. This blood test would also be useful in assessing the therapeutic value of convalescent plasma before infusion.
The Emory University researchers are now using the blood test to assess neutralising antibodies in people who get mild disease or remain asymptomatic. This would inform if such people are at a risk of re-infection. In a pandemic situation, it may also be better placed to offer “immunity passports”.
Commenting on the Emory study, of which he is an author, Ahmed says, “This study makes the important observation that COVID-19 patients rapidly generate neutralising antibodies against the virus. This is a very hopeful sign for protective immunity against re-infection in the recovered patients”. This, he says has “important implications for public health and for COVID-19 vaccines.”
“The La Jolla T-cell study links well with the Emory antibody study, where the key result is that RBD-binding antibody titres beautifully correlate to neutralising antibody titres in an individual,” adds Chandele, who was not part of either study.
These studies offer hope that vaccine developers will no longer fly blind.
Dr Shahid Jameel is a former Group Leader of Virology at ICGEB, New Dehi, India. He is currently CEO, DBT/Wellcome Trust India Alliance.