Antibodies can aid coronavirus infections

Antibodies can aid coronavirus infections, a new study has shown. The results have implications for the safety of a Covid-19 vaccine…

Vaccination works by educating the immune system to recognise threats it may encounter in the future. One of the first lines of defence is the production of protective antibodies. These are protein molecules shaped like the letter Y, the arms of which are “sticky”. They work by recognising and clinging tightly to specific structures present on the surfaces of potential invaders. This flags up the agent as hostile to the other components of the immune system, and can also disable key molecules that some pathogens rely on to infect and cause disease. As such, antibodies are normally a powerful immune weapon. 

But new research by the University of Minnesota’s Yushun Wan, published in the Journal of Virology, shows that antibodies can sometimes help, rather than hinder infections by certain coronaviruses. And if it also happens in Covid-19, it will make the search for a safe vaccine, or other antibody-based drug therapies, that much more challenging.

The problem is a phenomenon called antibody-dependent enhancement (ADE). Scientists working on a number of virus diseases, including dengue and respiratory syncytial virus (RSV), have known for many years that this can happen. When it does, the story is almost always the same: inappropriate or weakly-neutralising antibody responses elicited either by vaccines or infection by closely related viruses (known as viral serotypes) can exacerbate disease when the infection is encountered for real.

In essence, if the antibody generated in an infected or vaccinated host does not efficiently neutralise virus infectivity, the antibody can instead facilitate entry into antibody-recognising cells. This is known to happen with some coronaviruses, including the cat form of the disease, feline coronavirus, where immunisation with the viral ‘spike’ protein leads to more severe future infection due to the development of enhancing antibodies.

The Minnesota team have focussed on the recently-described Middle East respiratory syndrome coronavirus, called MERS-CoV. This causes a severe, frequently fatal, respiratory infection in humans after gaining entry to cells in the lungs by binding to a lung cell surface protein called DPP4.

An antibody that locks onto the part of the MERS-CoV virus that interacts with DPP4, the Minnesota team have found, will prevent the virus entering a DPP4-expressing lung cell. But, in a surprising twist of fate, decoration with this antibody endows the virus with the ability to infect immune cells instead.

The mechanism behind this apparently bizarre change of target hinges on a structure at one end of an antibody called the “Fc domain”. Certain immune cells express structures called “Fc receptors”, which recognise and bind onto the Fc domains of antibodies. This means that immune cells can effectively become susceptible to coronaviruses coated with antibodies. Alarmingly, the Minnesota scientists saw similar results with the SARS coronavirus too. But, just because the virus can potentially gain entry to immune cells via this mechanism, it may not be able to reproduce effectively within them. The present experiments did not test this specifically, so it remains to be proven explicitly.

Nevertheless, the authors of the new study point out that their data will inform future viral vaccine design. Vaccines that provoke neutralising antibody responses to regions of the coronavirus spike protein other than the receptor binding domain, they say, are optimal to reduce the likelihood of antibody-dependent enhancement. Spike-based subunit vaccines lacking the receptor binding domain, they suggest, are likely to be the best and safest vaccine contenders.