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Can Some Antibodies Worsen COVID-19? The Odd Situation of Enhancement

Antibodies are supposed to be the good guys. The proteins, built of distinctive Y-shaped pieces, enter the bloodstream early in infection, pouring out from plasma cells. They then latch onto molecules festooning pathogens and alert natural killer cells, which release a torrent of cytokines and complement, which are the biochemical weapons of an immune response.

Fighting infection is a complex business.

In a mysterious phenomenon called “antibody-dependent enhancement,” the proteins actually make matters worse, intensifying symptoms. When a vaccine elicits the errant antibodies, the backfiring is called “vaccine enhancement of disease.” We know these reactions exist, but still do not completely understand them.

The turncoat antibodies can be coaxed to appear in test tube experiments, but are elusive in a patient who is getting sicker. That is, there’s no clinical way to distinguish antibody-dependent enhancement from just a severe case of an infectious disease. And that can complicate analysis of a candidate vaccine. “Vaccine enhancement of disease” would show up in a clinical trial as more people receiving a vaccine getting sick than the participants getting placebo.

Reportedly that hasn’t happened for the candidate COVID-19 vaccines, but the data won’t be published until the phase 3 trials are completed.

In early clinical trials, the quick appearance of neutralizing antibodies in the blood plasma of treated participants was a good sign, a harbinger of a stronger immune response to come (because T cells control antibody production, and do much more). But will antibody enhancement appear as tens of thousands of people participate in the phase 3 trials?

During past epidemics, antibody enhancement arose in three situations:

• Lingering antibodies from previous infections from related pathogens
• Weak antibodies from convalescent plasma (from donors who’ve recovered)
• Weak antibodies elicited from a vaccine

Whatever the scenario, antibodies enhance disease by easing the entry of viruses into our cells – like opening the gates to a castle instead of fortifying them.

In a recent fascinating article in Nature, Ann Arvin and Herbert Virgin, from Vir Biotechnology, and their colleagues, reviewed historical cases of antibody dependent enhancement. They conclude that given the complexities, “it is sobering to take on the challenge of predicting antibody-dependent enhancement of disease caused by SARS-CoV-2.”

Consider the precedents, starting with cats.

Feline Coronavirus

Certain families of viruses are more likely to enhance an infectious disease. These include lentiviruses (HIV is one), flaviviruses (such as dengue, West Nile, Zika, and yellow fever), and coronaviruses.

Feline coronavirus typically doesn’t make cats very sick. But one strain can trigger painful feline infectious peritonitis, when rogue antibodies escort the viruses into not just lining cells, where they usually go, but also into the blobby macrophages that roam the body engulfing and digesting debris. The infected macrophages deliver viruses to many organs, causing severe symptoms. Researchers implicated the antibodies by injecting convalescent plasma from cats who’d survived the peritonitis into kittens, making them extremely sick.

The souped-up antibodies in the sick infected kittens bind to the viruses’ spikes, and then transport the viruses to macrophages, which the viruses enter. So instead of signaling an immune response, the antibodies enhance the infection.


Like the cat coronavirus infection, dengue in people is usually mild or asymptomatic. Rarely, though, dengue causes a hemorrhagic fever that can kill. Four varieties (serotypes) of a virus cause dengue (DEN 1-4).

Dengue is a classic example of antibody-dependent enhancement of disease because sometimes, a second infection is worse, not tamed.

In areas where dengue is endemic, about 0.5% of the population harbors low levels of antibodies from previous infections. Dengue is common in many parts of the world; the last case recorded in the US was in Texas in 2005.

Antibody-dependent enhancement of disease in dengue can occur when a person initially gets sick from one serotype and then is infected with another. The antibodies bind the stem portions of their Y-shaped subunits to a receptor (Fc) on macrophages, hitching rides and delivering viruses rather than signaling the immune response to destroy them.

A vaccine against all four dengue serotypes, Dengvaxia, has saved millions of lives. Controversy arose in 2016 after the vaccine was tested on young children who’d never been infected, in the Philippines, and 14 died. That number reached 600 by the end of 2019. But investigation by WHO researchers couldn’t distinguish whether they’d succumbed to vaccine-induced antibody enhancement, or the vaccine hadn’t worked at all and the children had contracted severe dengue. Age may have been a factor in the severe reactions. Today the vaccine is used in 20 nations and given to people aged 9 to 45.

Researchers also hypothesize that vaccination against dengue might increase the risk of antibody enhancement for a related virus – like yellow fever or Zika.

Respiratory Syncytial Virus (RSV)

Another striking example of vaccine enhancement of disease is RSV, which typically causes only mild cold symptoms. It can be serious in the immunocompromised, in people with heart or lung disease, premature infants, and older individuals.

A study from 1969 showed that children aged 6 to 11 months who had received vaccine for RSV fared worse when hospitalized for severe inflammation of the lungs (pneumonia) or the airways (bronchiolitis) than did unvaccinated children. Ten of 101 given vaccine had severe respiratory disease compared to 2 of 173 who weren’t vaccinated. Unexpected! The sick kids produced unusual antibodies that latched onto a fusion protein on the viral surfaces.

The researchers termed the response “vaccine-associated enhanced respiratory disease.” Eventually, four studies implicated the vaccine, but it had been an older, formalin-inactivated version. Newer RSV vaccines based on monoclonal antibodies are safe.


In 2009, some people who received vaccine against a novel H1N1 influenza strain developed severe respiratory disease attributed to the vaccine. The lungs of six middle-aged individuals who’d died showed glommed immune complexes suggesting that low levels of antibodies from past flu shots had bound to the stem parts of the hemagglutinin proteins that extend from the virus. Further vaccination tipped the scales and the antibodies somehow became enhancing.

Antibody and vaccine enhancement of disease are challenging to investigate. Besides both being clinically indistinguishable from severe cases of the infectious disease, there are no biomarkers, no specific combination of signs and symptoms that signal this response. We’ll just have to wait and see whether vaccine enhancement of COVID-19 happens. One reassuring observation is that SARS-CoV-2 binds to a different type of receptor – ACE2 – than the ones on macrophages.

The possibility, although unlikely, of vaccine enhancement of disease is yet one more reason not to rush development of COVID-19 vaccines.

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