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Researchers Say Discovery Could Lead to Better, More Accurate Antibody Tests

Work with new viral protein targets, scientists tell TheStreet, could greatly improve testing.
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One key to figuring out just how far Covid-19 has spread in any given population is antibody testing. The tests can also help in the fight against the disease by furthering vaccine and immune-response research. 

In addition, the tests can identify people who could donate blood containing antibody-rich plasma that could be used as a possible treatment for people severely ill with Covid-19.

The accuracy and limits, however, of the tests have been in question. 

The way the Covid antibody tests – also called serology tests – work is by searching for antibodies -- or proteins -- that are created when the body fought off a past infection of the novel coronavirus. Many of the Covid-19 antibody tests currently in use target what are known as “spike” proteins. Some also hunt for what are known as nucleocapsid antibodies – often referred to as “N” antibodies by scientists.

But these strategies have shortcomings. First, they only work several weeks after infection at the earliest, so they can’t be trusted to test patients recently infected. The tests’ sensitivity and specificity have also been questioned. 

Furthermore, some people may never produce the specific antibodies needed produce a positive result. Other people, meanwhile, may lose those antibodies after a short time. The tests may also give false positives for something as benign as a previous cold infection.  

“A positive test result shows you may have antibodies from an infection with the virus that causes Covid-19,” says the Centers for Disease Control and Prevention on its website, of the current antibody tests. “However, there is a chance a positive result means that you have antibodies from an infection with a virus from the same family of viruses (called coronaviruses), such as the one that causes the common cold.”

Some coronavirus researchers also question the role of the spike protein antibodies in the immune system's battle of Covid-19. This is critical, because many vaccines in development target the spike protein.

But this could all change soon. A team of researchers at Hong Kong University’s medical school have recently found two new viral protein targets that could be used in antibody tests that are more accurate and able to identify infection sooner than many current antibody tests. The tests could also potentially tell whether someone was infected with the virus, or vaccinated, once a vaccine is created.

But first a warning for those who forgot their high school biology: These two viral proteins are more difficult to visualize than the spike proteins – the ones that refer to the virus' protruding spikes that make it look like pointy ball. Instead, the new targets sound a lot like they could be names of rebel “Star Wars” robots: “ORF8” and “ORF3b.”

“Yes, we need marketing lessons; we talk in science code,” joked Sophie Valkenburg, a research assistant professor at Hong Kong University’s Pasteur Research Pole, in an email to TheStreet. "ORF," Valkenburg further explained, means "open reading frame" and is just a generic name for proteins with unknown functions and the number they appear in order in the virus. 

"These ORFs are non structural, so they don’t make up part of the virus and are only there during replication and infection."

Valkenburg, who led the research team, says the newly discovered targets could help usher in a new generation of better tests, help with vaccine development and improve research into Covid-19.

Technically speaking, the two new targets, ORF8 and ORF3b, are genome sequences that are translated into viral proteins, according to Niloufar Kavian-Tessler, another researcher on the team. And, though the role of the viral proteins is still unknown she said, their antibodies are solid evidence of past infection with Covid-19. Their antibodies are also unlikely to be confused with other past viral infections.

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“These targeted proteins are quite unique to SARS-CoV-2,” said Kavian-Tessler in an email to TheStreet, adding that team found they won't give positive results for old cold coronavirus infections.

For more on the findings and their potential implications for antibody testing, vaccine research and more, TheStreet spoke with Valkenburg and Kavian-Tessler by email this week. Following is a lightly edited version of the exchange. 

TheStreet: So, it sounds like ORF8 is specific to similar bat-carrying coronaviruses, but not those that cause the common cold, correct?

Valkenburg: ORF8 can be found in some bat viruses, but not common cold viruses, hence it is a very “clean” response to look for as evidence of SARS-CoV-2 infection. ORF3b has different forms in other common cold viruses, but little to no (homologous relationship to the viral proteins in cold viruses).

TheStreet: From your research, it sounds as well like these two viral proteins also can be targets for more accurate antibody testing?

Valkenburg: Yes, these tests are more accurate, as the background immunity is less. Most adults have had a common cold virus, to which they have pre-existing immunity, making the background immunity high and test sensitivity lower. 

TheStreet: How useful do you think current antibody tests on the market are? How accurate are they?

Valkenburg:The timing of accuracy for serological testing depends on the time of infection, most of current tests only work two weeks after infection. We found we could accurately detect evidence of infection within 14 days at 86.4% sensitivity, and 96.5% sensitivity identification of patients at early, and late time points with 99.5% specificity, with no false positives. 

TheStreet: There's been a lot of talk about antibodies fading after a certain amount of time; is it possible that tests targeting ORF8 and ORF3b could pick up a past infection at a later time after infection than the current tests can?

Valkenburg: Yes. We see that ORF8 and ORF3b have the narrowest change with time and were the most stable long-term antibody response. The time of waning will be different for different antibodies, as the proteins within the virus are at different amounts, and some may stick around for longer. A response fading with time is totally expected and happens with all virus infections, otherwise our immune system would be bigger than our bodies; we make a response, fight the infection, and it contracts, ready for the next fight, and remembering what it saw for future rounds.

TheStreet: Many vaccine candidates target the spike protein. Does this finding potentially have any impact on vaccine research? 

Valkenburg: Yes, the spike is still a very worthy vaccine target, as antibodies to the spike can block infection. But the “N” antibodies make a larger response, and other targets like ORF3b and ORF8 can make backup responses when neutralization hasn’t been effective enough. Whole virus-inactivated vaccines may stimulate these responses, while the spike alone will not. This test could be used to determine if someone was vaccinated (by finding spike-only antibodies) or infected (by finding ORF3b and ORF8 antibodies). 

TheStreet: Finally, how long would it take, do you think for a test maker to develop an antibody test targeting these viral proteins, ORF8 and ORF3b? 

Kavian-Tessler: The technique we used in the paper is called “LIPS” and is not easy to set up by any diagnostic lab. We are currently testing the possibility of switching to a more common and easy method ... so that the detection of ORF3b and ORF8 antibodies can be more widely tested, including in resource poor countries. If an experienced lab would want to set up the LIPS ORF3b and ORF8 test, we think that it would take several weeks to set it up fully. 

This story has been updated. Correction: Sophie Valkenburg's name was misspelled in earlier versions of this story. TheStreet regrets the error.