Antibody Dependent Enhancement and SARS-CoV-2

When Developing a SARS-CoV-2 Vaccine, Researchers Need to Consider that Antibodies May Enhance Infection Rather than Provide Protection

There is encouraging news from recent clinical trials of SARS-CoV-2 vaccines, including several candidate vaccines that induce neutralizing antibodies with no apparent adverse effects. Their protective efficacy at preventing infections is not yet known, but will be ultimately determined by phase 3 trials. However, there are other potential concerns over vaccine outcomes, one of which is the possibility of inducing antibodies that make infection outcomes worse. One such phenomenon is called antibody dependent enhancement (ADE).

The poster child for ADE is, of course, dengue virus (DENV). Infection with one of the four common serotypes of DENV results in worse outcomes after later infection by a different serotype. Indeed, some tetravalent dengue vaccines mimic a first infection with DENV and cause worse outcomes upon later infection, even though neutralizing antibodies are elicited. It is speculated that a successful immune response to DENV requires a CD8+ T cell response. The recombinant vaccine contains only DENV envelope glycoproteins in the backbone of yellow fever attenuated 17D strain, which can be poor in inducing CD8+ T cell response. Indeed, live attenuated tetravalent DENV vaccines (National Institutes of Health ), which contain all the virion proteins, have provided enhanced protection.

How does ADE work? The most common mechanism appears to occur when a non-neutralizing or poorly neutralizing antibody binds to a virus particle. The fragment crystallizable region (Fc) of the antibody interacts with Fc receptors (FcR) expressed on certain immune cells (i.e., macrophages, B cells, Follicular dendritic cells, natural killer cells, and neutrophils) and some of the complement proteins. This facilitates viral entry into immune cells, shifting the tropism of the virus. If the virus can replicate in macrophages or other FcR-containing cell, it provides new opportunities for viral replication and spreads into neighboring cells. In addition, infection of macrophages can cause adverse immune activities. This phenomenon is often observed when antibody concentrations decrease as a result of waning immunity. In addition, an antibody may neutralize potently at high concentrations but cause enhancement of infection at sub-neutralizing concentrations.

Another way in which vaccination can result in worse disease is by enhanced respiratory disease (ERD). This was seen in children vaccinated against respiratory syncytial virus and involves non-neutralizing antibodies forming complexes that get deposited in airways, thus causing inflammation. There also appears to be priming of cell-mediated immunity towards a Th2 inflammatory type of response.

What are the reasons for thinking that ADE will or will not be a problem with SARS-CoV-2? One example of a coronavirus infection for which ADE seems to present a problem is feline infectious peritonitis virus (FIPV). Kittens inoculated with a vaccinia recombinant vaccine containing the FIPV spike protein developed high levels of non-neutralizing antibodies, but only very low levels of neutralizing antibodies. They suffered far worse infection outcome at a much higher incidence. This phenomenon was not observed when other viral proteins were used instead of spike protein; yet, it should be pointed out that FIPV is an alphacoronavirus, unlike SARS-CoV-2, a betacoronavrus.

There are some data on ADE with SARS-CoV-2-related betacoronaviruses. One study showed that a candidate vaccine containing SARS-CoV-1 spike protein elicited neutralizing antibodies in vaccinated mice. The antibodies, however, potentiated infection of B cells by an FcR-mediated mechanism.  Despite this, the vaccine provided protection to mice, so even though it elicited detectable ADE, it did not cause worse disease. A similar finding was made in hamsters.

ADE activities could be found in SARS-CoV-1-infected humans. Polyclonal antisera or of monoclonal antibodies that bind viral spike (S) protein can facilitate uptake by human monocytic cells via their Fcγ receptors (FcγRs). In the case of Middle Eastern respiratory syndrome coronavirus (MERS-CoV), Fc-mediated targeting has been observed with neutralizing antibodies that bind directly to the receptor-binding domain of S protein. For both viruses, this phenomenon is dependent on antibody concentration.

Low concentrations facilitated ADE, while high concentrations neutralized the virus. In SARS-CoV-1-infected macaques, antibodies to spike protein were associated with fatal acute lung injury, attributed to alterations in pro-inflammatory immune responses. Yan and colleagues found that a monoclonal neutralizing antibody to MERS blocked entry of a MERS-CoV pseudovirus into a typical target cell but facilitated viral entry into cells expressing FcR, such as macrophages, by a canonical viral entry pathway. The effect was attributed to the antibody loosening the spike protein trimeric structure, making it more accessible to proteolytic processing.

What about SARS-CoV-2? What of a vaccine based upon the spike protein alone? Is there a possibility that ADE may play a pathogenic role in natural infection? The reality is that there are far more questions about these possibilities than there are actual data. Epidemiological studies investigating ADE in individuals with multiple SARS-CoV-2 infections or cross-reactivity to common-cold-causing CoVs will likely take several years. One indication comes from the use of convalescent plasma. Administration into COVID-19 patients appeared to be generally safe. This does not necessarily reflect what will happen after vaccination with spike antibody protein or inactivated vaccines. Inoculation with whole inactivated virus protected macaques against subsequent challenge and showed no signs of ADE. Reducing the risk of vaccine-associated enhanced respiratory disease or ADF of replication involves induction of high-quality functional antibody responses and Th1-biased T-cell responses. If antibodies against SARS-CoV-2 with ADE potential are detected, vaccine development efforts can leverage the full suite of modern technologies around epitope mapping, protein design, adjuvant design and delivery to maximize safety. Currently, there are no data showing direct evidence of ADE for SARS-CoV-2 candidate vaccines. The answers will likely come from phase 3 trials, a number of which are underway, in recruitment, or planned. Results are most eagerly awaited.


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